Patterning and Cell Type Specification in the Developing CNS and PNS: Comprehensive Developmental Neuroscience

By Academic Press

The genetic, molecular, and cellular mechanisms of neural development are essential for understanding evolution and disorders of neural systems. Recent advances in genetic, molecular, and cell biological methods have generated a massive increase in new information, but there is a paucity of comprehensive and up-to-date syntheses, references, and historical perspectives on this important subject. The Comprehensive Developmental Neuroscience series is designed to fill this gap, offering the most thorough coverage of this field on the market today and addressing all aspects of how the nervous system and its components develop. Particular attention is paid to the effects of abnormal development and on new psychiatric/neurological treatments being developed based on our increased understanding of developmental mechanisms. Each volume in the series consists of review style articles that average 15-20pp and feature numerous illustrations and full references. Volume 1 offers 48 high level articles devoted mainly to patterning and cell type specification in the developing central and peripheral nervous systems.

• Series offers 144 articles for 2904 full color pages addressing ways in which the nervous system and its components develop
• Features leading experts in various subfields as Section Editors and article Authors
• All articles peer reviewed by Section Editors to ensure accuracy, thoroughness, and scholarship
• Volume 1 sections include coverage of mechanisms which: control regional specification, regulate proliferation of neuronal progenitors and control differentiation and survival of specific neuronal subtypes, and controlling development of non-neural cells

• Language: English
• Publisher: Academic Press
• Release date: May 6, 2013
• ISBN: 9780123973481

Book preview

Comprehensive Developmental Neuroscience: Patterning and Cell Type Specification in the Developing CNS and PNS

Editors-in-Chief

Professor John L.R. Rubenstein

Department of Psychiatry, University of California at San Francisco, San Francisco, CA, USA

Professor Pasko Rakic

Duberg Professor of Neurobiology and Neurology, Director Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA

Table of Contents

Cover image

Title page

Copyright

Editors-in-Chief

Section Editors

Contributors

Introduction to Comprehensive Developmental Neuroscience

I: Induction and Patterning of the CNS and PNS

Chapter 1. Telencephalon Patterning

1.1 Introduction

1.2 Telencephalon Induction

1.3 Overview of Early Telencephalic Subdivisions

1.4 Establishing Dorsal Versus Ventral Domains

1.5 Boundary Structures as Organizing Centers and CR Cell Sources

1.6 Subdividing Ventral Domains

1.7 Conclusions

Acknowledgments

References

Chapter 2. Morphogens, Patterning Centers, and their Mechanisms of Action

2.1 General Principles of Morphogen Gradients

2.2 Local Signaling Centers and Probable Morphogens in the Telencephalon

2.3 BMPs as Morphogens in Telencephalic Patterning

2.4 FGFs as Morphogens in Telencephalic Patterning

2.5 Interactions Among Signaling Centers in Telencephalic Patterning

2.6 Morphogens in Human Brain Disease

References

Chapter 3. Midbrain Patterning: Isthmus Organizer, Tectum Regionalization, and Polarity Formation

3.1 Function and Development of the Midbrain

3.2 Midbrain Regionalization

3.3 Isthmus Organizer

3.4 Isthmic Organizer and Tectum Polarity

3.5 Conclusion

References

Chapter 4. Area Patterning of the Mammalian Cortex

4.1 Introduction

4.2 Cortical Divisions and Components

4.3 Naturally Occurring Differences in Area Patterning

4.4 Extrinsic Influences on Area Patterning

4.5 Intrinsic Genetic Mechanisms Regulating Arealization

4.6 Extent of Genetic Specification of Area-Specific Properties

4.7 Regional Patterning of the Cerebral Cortex

4.8 Conclusions

Acknowledgments

References

Chapter 5. The Formation and Maturation of Neuromuscular Junctions

Abbreviations

5.1 Introduction

5.2 Neuromuscular Junctions are Comprised of Several Cell Types

5.3 The Formation of Neuromuscular Junctions Involves Bidirectional Signaling Among Cell Types

5.4 Formation of a Differentiated Postsynaptic Membrane: The Agrin-MuSK-ACh Hypothesis

5.5 Neuromuscular Synapse Elimination

5.6 Structural and Functional Changes at Neuromuscular Junctions During Synapse Elimination

5.7 Mechanisms of Synapse Elimination: Activity-Dependent Competition

5.8 Summary

References

Chapter 6. Neural Induction of Embryonic Stem/Induced Pluripotent Stem Cells

6.1 Introduction to Embryonic Stem Cells and Induced Pluripotent Stem Cells

6.2 Introduction to ES and iPS Neural Induction

6.3 Neural Progenitor Cells

6.4 Differentiation to Specific Regional Identities

6.5 Differentiation to Neural Crest Progenitor Cells

6.6 Direct Conversion of Fibroblasts to Neurons

6.7 Clinical Applications

6.8 Review

References

Chapter 7. Spinal Cord Patterning

Nomenclature

7.1 Introduction

7.2 Major Concepts of Spinal Cord Patterning

7.3 Dorsoventral Patterning

7.4 Rostrocaudal Patterning

7.5 LIM/bHLH Factors and the Combinatorial Code

7.6 Cell–Cell Interactions

7.7 Glia in the Spinal Cord

7.8 Human Diseases of Spinal Cord Patterning

7.9 Lessons from Spinal Cord Patterning for Disease Modeling and Regenerative Medicine

7.10 Summary and Unanswered Questions

Glossary

References

Chapter 8. Patterning of the Diencephalon

8.1 Introduction

8.2 Morphologic Assumptions (Models) Underpinning Thought on Diencephalic Patterning

8.3 Subdivisions of the Developing Diencephalon in the Prosomeric Model

8.4 Diencephalic Molecular Regionalization Preceding the Formation of the Zona Limitans (Prepatterning)

8.5 Formation of the Zona Limitans

8.6 Molecular Patterning of the Diencephalon after Zona Limitans Formation

References

Chapter 9. Neural Induction Embryonic Stem Cells

9.1 Embryonic Origins of the Nervous System

9.2 Default Model for Neural Induction

9.3 Mammalian Embryonic Stem Cells

9.4 Early Neural Patterning in the Vertebrate Embryo

9.5 Establishment of the Anteroposterior Polarity in the Embryonic Neuraxis

9.6 Establishment of the Dorso–Ventral Polarity in the Embryonic Neuraxis

9.7 Establishment of the Right–Left Polarity in the Embryonic Neuraxis

9.8 Early Patterning of Neuralized ESC

9.9 Temporal Regulation of Neural Patterning in ESCS

References

Chapter 10. Plan of the Developing Vertebrate Nervous System: Relating Embryology to the Adult Nervous System (Prosomere Model, Overview of Brain Organization)

10.1 Introduction

10.2 Neural Plate, Clonal Structure, and Topologic Spatial Dimensions

10.3 Neural Tube

References

Chapter 11. Cerebellar Patterning

11.1 Introduction

11.2 Three Types of Cerebellar Patterning in Adult Mammals

11.3 Formation of Cerebellar Patterning

References

Chapter 12. Hox Genes and Neural Patterning in Drosophila

12.1 Introduction

12.2 Organization and Development of the Drosophila Nervous System

12.3 Hox Genes and Patterning of the PNS

12.4 Hox Genes in the Development of the Embryonic CNS

12.5 Hox Genes in the Development of the Postembryonic CNS

12.6 Genetic Interactions Between Hox Genes in Neural Patterning

12.7 Evolutionary Conservation of Hox Gene Expression and Function in Neural Development

See also

Acknowledgment

References

Chapter 13. Induction and Patterning of Neural Crest and Ectodermal Placodes and their Derivatives

13.1 Introduction

13.2 Neural Crest and Placodes: Derivatives of the Neural Plate Border

13.3 Neural Crest

13.4 Ectodermal Placodes

13.5 Conclusions

Acknowledgments

References

II: Generation of Neuronal Diversity

Chapter 14. Cell Biology of Neuronal Progenitor Cells

14.1 Introduction

14.2 Location of Neuronal Progenitors

14.3 Creating Different Types of Neuronal Progenitor Cells

14.4 Cell Lineage Analysis Reveals the Fate of Individual Neuronal Progenitor Cells

14.5 Structure and Dynamism of Neuronal Progenitor Cells

14.6 Asymmetric Cell Division for Neuronal Diversity

14.7 Progenitor Microenvironment and Regulating Neuronal Progenitor Number

14.8 Summary

Acknowledgments

References

Chapter 15. Cell Cycle Regulation in Brain Construction

15.1 Introduction

15.2 Unique Aspects of Cell Division in the Forebrain Neuroepithelium

15.3 Elements of Cell Cycle Control

15.4 Spatial and Temporal Differences in Cell Cycle Regulation During Cortical Construction

15.5 G1-Phase Regulation as Link Between External Environment and Internal Cell Cycle Machinery

15.6 Summary: The Relationship of Proliferation Regulation to Cortical Size and Structure

Acknowledgment

References

Chapter 16. Regulation of Neuronal Survival by Neurotrophins in the Developing Peripheral Nervous System

16.1 Neuronal Death in the Developing Nervous System

16.2 Neurotrophic Theory and Neurotrophic Factors

16.3 Retrograde Trophic Support from Innervation Targets

16.4 Retrograde Trophic Support from Cells En Route to Innervation Targets

16.5 Anterograde Trophic Support

16.6 Autocrine Trophic Support

16.7 Cytotoxic Actions of Neurotrophins on Neurons

References

Chapter 17. Notch and Neural Development

17.1 History of Notch Signaling

17.2 Molecular Mechanisms

17.3 Signaling Diversity and cis-Inhibition

17.4 Timing and Feedback Are Everything

17.5 Notch and the Maintenance of Neural Stem Cells During Nervous System Development

17.6 Notch and the Generation of Interneuron Diversity

17.7 Postnatal Neuro- and Gliogenesis

17.8 Notch and Astroglial Cell Fate

17.9 Notch and Neuronal Migration

17.10 Notch and Dendrite Morphogenesis

17.11 Synaptic Plasticity and Notch Signaling

17.12 Embryonic Stem Cells and Clinical Perspectives

17.13 Conclusion

References

Chapter 18. bHLH Factors in Neurogenesis and Neuronal Subtype Specification

18.1 Overview of Review Content

18.2 Identification of Neural bHLH Transcription Factors: History and Evolutionary Conservation Between Fly and Mammal

18.3 bHLH Factor Function in Neuronal Differentiation

18.4 Functions of bHLH Transcription Factors in Neuronal Subtype Specification

18.5 Molecular Characteristics of bHLH Transcription Factors

18.6 Transcriptional Targets of bHLH Factors

18.7 Transcriptional Regulation of bHLH Gene Expression

18.8 Signaling Pathways Regulating bHLH Factors

18.9 Posttranslational Control of the bHLH Transcription Factor Function

18.10 Perspective

References

Chapter 19. Environmental Cues and Signaling Pathways that Regulate Neural Precursor Development

19.1 Introduction

19.2 Signaling Pathways that Regulate Neural Precursor Self-Renewal and Maintenance

19.3 Signaling Neurogenesis: Multiple Cues and Multiple Mechanisms

19.4 The Neuron–Glial Switch

19.5 Implications for Human Neural Development

See also

References

Chapter 20. Specification of Neural Crest- and Placode-Derived Neurons

20.1 The Placode-Derived Peripheral Nervous System

20.2 The Neural Crest-Derived PNS

20.3 Conclusions

References

Chapter 21. The Specification and Generation of Neurons in the Ventral Spinal Cord

21.1 Introduction and General Organization

21.2 Induction of Spinal Cord Tissue and Initiation of Regional Pattern

21.3 Spinal Cord Neurogenesis

21.4 The Generation of Differentiated Neuronal Cell Subtypes

References

Chapter 22. Neurogenesis in the Cerebellum

22.1 Introduction to the Cerebellum

22.2 Model Organisms Used to Study Cerebellar Neurogenesis

22.3 Overview of Cerebellar Development

22.4 Establishing the Cerebellar Territory

22.5 The Cerebellar Rhombic Lip and Its Derivatives

22.6 The Cerebellar Ventricular Zone and Its Derivatives

22.7 Cerebellar Stem Cells

22.8 Abnormal Cerebellar Neurogenesis and Human Cerebellar Disorders

22.9 Conclusions and Future Perspectives

References

Chapter 23. The Generation of Midbrain Dopaminergic Neurons

23.1 Introduction

23.2 The Anatomy of the Mesencephalon

23.3 The Development of Midbrain Dopaminergic Neurons – General Overview

23.4 Formation of the Midbrain Region

23.5 The Role of Signaling Centers and Secreted Factors

23.6 Generation of Midbrain Dopaminergic Progenitors: Specification and Proliferation

23.7 Generation of Immature and Mature Midbrain Dopaminergic Neurons

23.8 The Terminal Differentiation of the Mature Dopamine Neuron

23.9 Maintenance of Midbrain Dopaminergic Neurons

23.10 Perspectives

Acknowledgments

References

Chapter 24. Neurogenesis in the Basal Ganglia

24.1 Introduction

24.2 Organization of Embryonic Subdivisions and Their Relationship to Mature Structures and Cell Types

24.3 Regional Specification of Subdivisions of the Embryonic Basal Ganglia

24.4 Generation Neuronal Subtypes

References

Chapter 25. Specification of Cortical Projection Neurons: Transcriptional Mechanisms

25.1 Introduction

25.2 Neocortical Progenitors

25.3 Specification of Neocortical Projection Neuron Progenitor Domain

25.4 Molecular Controls over Neocortical Projection Neuron Subtype Specification and Development

25.5 Areal Diversity of Neocortical Projection Neurons

25.6 Progressive Restriction and Refinement of Cortical Projection Neuron Subtypes

25.7 Conclusions

References

Chapter 26. The Generation of Cortical Interneurons

26.1 Diversity of Mature Cortical Interneurons

26.2 Developmental Origin of Cortical Interneurons

26.3 Place and Time of Origins of Cortical Interneurons

26.4 Migration of Cortical Interneurons

26.5 Postnatal Cortical Interneuron Development

Acknowledgments

References

Chapter 27. Specification of Retinal Cell Types

27.1 Introduction

27.2 RPC Competence

27.3 Intrinsic Regulation of Retinal Development

27.4 Extrinsic Regulation of Retinogenesis

27.5 Human Retinal Disease

27.6 Perspectives

See also

Glossary

References

Chapter 28. Neurogenesis in the Postnatal VZ-SVZ and the Origin of Interneuron Diversity

28.1 Newborn Neurons Are Generated in the VZ–SVZ of the Adult Brain

28.2 Identification and Origin of Adult Neural Stem Cells

28.3 OB Interneurons Are Heterogeneous

28.4 Spatial Specification of OB Interneuron Identity

28.5 Temporal Regulation of OB Interneuron Production

28.6 Conclusion

Acknowledgments

References

Chapter 29. Neurogenesis in the Damaged Mammalian Brain

29.1 Introduction

29.2 Persistent Versus Injury-Induced Neurogenesis in the Adult Brain

29.3 Neurogenesis in the Injured Brain

29.4 Identity, Integration, and Extent of Regeneration of New Neurons

29.5 Contribution of Injury-Induced Neurogenesis to Functional Recovery

29.6 How Widespread Is Injury-Induced Neurogenesis?

29.7 Cellular Origins of Injury-Induced Neurogenesis

29.8 Mechanisms Underlying Injury-Induced Neurogenesis

29.9 Link between Neurodegeneration and Neurogenesis

29.10 Neurovascular Niche

29.11 Nonneurogenic Roles of Adult NPCs in Brain Repair

29.12 Future Perspectives

Acknowledgments

References

Chapter 30. Neurogenesis in the Nematode Caenorhabditis elegans

30.1 Introduction

30.2 Neuronal Cell Lineages and Neuron Classification

30.3 Genes Controlling Lineage Decisions

30.4 Genes Controlling Neuron Class Specification

30.5 Genes Controlling Neuron Subclass Specification

30.6 Linking Neuronal Class Specification to Lineage

30.7 Conclusions and Perspectives

Acknowledgments

References

Chapter 31. Development of the Drosophila Embryonic Ventral Nerve Cord: From Neuroectoderm to Unique Neurons and Glia

31.1 Introduction

31.2 Breaking the Homogeneity (Patterning of the Neuroectoderm)

31.3 Homologous Neuromeres: Same but Different

31.4 The Chosen One (Lateral Inhibition)

31.5 Unequal Legacy (Asymmetric Cell Division)

31.6 One Thing at a Time (the Temporal Cascade)

31.7 Regulation of Neuroblast Proliferation

31.8 The Role of Programmed Cell Death in the Drosophila Embryonic VNC

31.9 Finishing the Picture (Specification of Unique Cell Types)

31.10 Conclusions

31.11 Outstanding Issues

Acknowledgments

References

Chapter 32. Neurogenesis in Zebrafish

32.1 Neural Plate Induction and Patterning

32.2 Establishment of the Primary Neuronal Scaffold

32.3 Secondary Neurogenesis

32.4 Adult Neurogenesis and Plasticity

References

III: Development of Glia, Blood Vessels, Choroid Plexus, Immune Cells in the Nervous System

Chapter 33. ‘Glial’ Biology: Has it Come to the Beginning of the End?

33.1 Brief Summary of Section Chapters

Chapter 34. Neural Stem Cells Among Glia

34.1 Introduction

34.2 NSCs Among Glia in the Developing Brain

34.3 Developing Human Neocortex

34.4 NSCs Among Glia in the Postnatal Brain

34.5 Link Between Embryonic and Adult Glial Cells That Function as NSCs

34.6 Origin of Oligodendrocytes from RG and Adult SVZ Astrocytes

34.7 Evolutionary Perspective

34.8 Perspective for Brain Repair

34.9 Conclusion

Acknowledgments

References

Chapter 35. Structure and Function of Myelinated Axons

35.1 Introduction

35.2 Evolution of the Myelinated Axon

35.3 Myelinating Glial Cells and Axoglial Interactions

35.4 Nodes of Ranvier: Structure, Composition, and Function

35.5 Assembly of Nodes of Ranvier

35.6 Long-Term Maintenance of Nodes in the PNS and CNS

35.7 Function of Nodes in AP Propagation and Initiation

35.8 Nodes of Ranvier in Nervous System Disease and Injury

35.9 Conclusions and Outlook

References

Chapter 36. Mechanisms of Astrocyte Development

36.1 Introduction: Generating Astrocyte Diversity During Gliogenesis

36.2 Origins of Astrocytes in the Neural Tube

36.3 Cell-Extrinsic Influences in Astrogenesis: Patterning and Beyond

36.4 General Mechanisms (Cell-Intrinsic Regulation) of Astrocytogenesis by Transcription Factors

36.5 Conclusion and Future Directions

Acknowledgments

References

Chapter 37. Specification of Macroglia by Transcription Factors: Oligodendrocytes

37.1 Introduction

37.2 Determinants of Oligodendroglial Fate

37.3 Determinants of Oligodendroglial Identity

37.4 Determinants of Progenitor State Maintenance

37.5 Determinants of Progression from the Progenitor State

37.6 Determinants of Terminal Differentiation and the Fully Differentiated State

37.7 Concluding Remarks and Perspectives

References

Chapter 38. Specification of Macroglia by Transcription Factors: Schwann Cells

38.1 Specification of Schwann Cells from Neural Crest

38.2 Immature Schwann Cells and Acquisition of a Myelinating Phenotype

38.3 Neuregulin/ErbB Signaling

38.4 Ca2+ Signaling and NFAT

38.5 Lgi4–Adam22 Interactions in Myelination

38.6 Integration of Signaling Pathways at Specific Response Elements

38.7 Transcription Factor Tug-of-War; Mutually Antagonistic Relationships Between Egr2 and jun/Notch

38.8 Pathogenic Signaling Pathways and Transcription

See also

References

Chapter 39. Signaling Pathways that Regulate Glial Development and Early Migration – Oligodendrocytes

39.1 Introduction

39.2 Signaling Pathways Regulating the Initial Appearance of Oligodendrocytes

39.3 Regulation of OPC Dispersal

39.4 Regulation of Oligodendrocyte Precursor Differentiation

39.5 Conclusion

References

Chapter 40. Signaling Pathways that Regulate Glial Development and Early Migration – Schwann Cells

40.1 Introduction

40.2 Overview of Schwann Cell Development

40.3 Developmental Potential and Schwann Cell Plasticity

40.4 Major Differences Among Migrating Neural Crest Cells, SCPs, and iSchs

40.5 Gliogenesis from Crest Cells: The Appearance of SCPs

40.6 NRG1 and Notch Signaling in SCPs

40.7 Schwann Cell Generation and the Architectural Reorganization of Peripheral Nerves

40.8 SCPs and Early Schwann Cells Control Neuronal Survival, Nerve Fasciculation, and Synapse Formation

40.9 Schwann Cells in Late Embryonic Nerves

40.10 Signals that Drive Schwann Cell Proliferation In Vivo

40.11 Factors that Drive Schwann Cell Division In Vitro

40.12 Control of Schwann Cell Death In Vivo

40.13 Radial Sorting and the Onset of Myelination

Acknowledgments

References

Chapter 41. Microglia

Abbreviations

41.1 Introduction

41.2 Origin of Microglia

41.3 Microglia as Dynamic Cells in the CNS

41.4 Microglia Activation

41.5 Microglia Interactions with Other Cells

41.6 Microglia and Disease

41.7 Concluding Remarks

References

Chapter 42. Ependyma, Choroid

42.1 Introduction

42.2 Choroid Plexus

42.3 Ependyma

42.4 Summary

References

Chapter 43. Meninges and Vasculature

43.1 Structure and Function of the Meninges

43.2 Function of the Meninges During Brain Development

43.3 Vascularization of the Developing Brain

43.4 Conclusions

References

Chapter 44. Neuron–Glial Interactions: Schwann Cells

Abbreviations

44.1 Neuronal and Glial Coevolution: Glial Cells Associate with Neuronal Processes

44.2 The Structure and Composition of Peripheral Myelin

44.3 Reciprocal Axon–Glia Signaling Controls Myelination

44.4 Long-Term Support of Axon Function by Associated Glial Cells

44.5 Diseases Caused by Perturbed Myelination

References

Chapter 45. Neuron–Glial Interactions: Neurotransmitter Signaling to Cells of the Oligodendrocyte Lineage

45.1 Introduction

45.2 Distinguishing Characteristics of OPCs, Premyelinating Oligodendrocytes, and Mature Oligodendrocytes

45.3 Neurotransmitter Signaling Within the Oligodendrocyte Lineage: Glutamate

45.4 Neurotransmitter Signaling Within the Oligodendrocyte Lineage: GABA, Acetylcholine, and ATP

45.5 Synaptic Signaling Between Neurons and OPCs

45.6 Oligodendrocyte Lineage Cells in the Context of Disease and Injury

45.7 Conclusions/Future Directions

References

Chapter 46. Invertebrate Glia

46.1 Glial Studies in Invertebrates

46.2 Glial Electrophysiology in the Medicinal Leech Hirudo medicinalis

46.3 Roles for Glia in Sensory System Development, Synaptogenesis, and Behavior in C. elegans

46.4 Overview of Glial Cell Biology in Drosophila

46.5 Lineages of Glia in the Drosophila Embryo

46.6 Morphological and Molecular Subtypes of Embryonic CNS Glia

46.7 Growth, Proliferation, and Lineages of Larval Glia

46.8 Molecular Biology of Glial Cell Fate Specification and Subtype Diversity

46.9 Roles for Drosophila Glia in Nervous System Development and Function

46.10 Glia Engulf Neuronal Cell Corpses During Embryonic CNS Development

46.11 Sculpting Neural Circuits Through Engulfing Actions of Glial Cells

46.12 Growth Factor Receptor Signaling in Glial Proliferation and Ensheathment of Axons

46.13 Formation, Maintenance, and Function of the BBB

46.14 NT Recycling and Suppression of Excitotoxicity

46.15 Information Processing and Behavior – Glia Regulate Circadian Motor Output

46.16 Closing Comments

References

Chapter 47. Nonmammalian Model Systems: Zebrafish

47.1 History and Attributes of the Zebrafish Model System

47.2 Zebrafish Glial Classification

47.3 Zebrafish Oligodendrocyte Development

47.4 Zebrafish Peripheral Glia

47.5 Zebrafish Radial Glia

47.6 Conclusion

References

Chapter 48. New Approaches in Glial Biology: Imaging Neuroglial Pathology In Vivo

48.1 Development of Neuroimaging

48.2 Imaging Neuroglial Pathology in Neurological Disease Models

48.3 Perspectives for Imaging Neuroglial Pathology

Acknowledgments

References

Index

Copyright

Academic Press

Academic Press is an imprint of Elsevier

525 B Street, Suite 1900, San Diego, CA 92101-4495, USA

32 Jamestown Road, London NW1 7BY, UK

225 Wyman Street, Waltham, MA 02451, USA

First edition 2013

Copyright © 2013 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher.

Permissions may be sought directly from Elsevier’s Science & Technology Rights, Department in Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: [e-mail]. Alternatively, visit the Science and Technology Books website at www.elsevierdirect.com/rights for further information.

Notice

No responsibility is assumed by the publisher for any injury and/or damage to persons, or property as a matter of products liability, negligence or otherwise, or from any use or, operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress

ISBN: 978-0-12-397265-1

For information on all Academic Press publications visit our website at elsevierdirect.com

Typeset by SPi Global www.spi-global.com

Printed and bound in the USA

13 14 15 16 17 10 9 8 7 6 5 4 3 2 1

Editors-in-Chief

Professor John L.R. Rubenstein

Department of Psychiatry, University of California at San Francisco, San Francisco, CA, USA

Professor Pasko Rakic

Duberg Professor of Neurobiology and Neurology, Director Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA

Section Editors

Professor Arturo Alvarez‐Buylla,    Department of Neurological Surgery and The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research University of California, San Francisco, School of Medicine, San Francisco, CA, USA

Professor Yehezkel Ben‐Ari,    Institute of Neurobiology of the Mediterranean Sea (INMED) AND CEO of Neurochlore Company, INSERM (the French Institute of Health and Medical Research), Marseille, Department of the Bouches du Rhone, France

Professor Kenneth Campbell,    Divisions of Developmental Biology and Neurosurgery Cincinnati Children’s Hospital Medical Center University of Cincinnati College of Medicine Cincinnati, OH, USA

Professor Hollis T. Cline,    Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA, USA

Dr. François Guillemot,    Division of Molecular Neurobiology MRC National Institute for Medical Research, London, UK

Professor Takao Hensch,    Department of Molecular and Cellular Biology Harvard University, Cambridge, MA, USA

Professor Pat Levitt,    Zilkha Neurogenetic Institute and Department of Cell and Neurobiology, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA

Dr Oscar Marín,    Instituto de Neurociencias, CSIC and Universidad Miguel Hernández, Alicante, Spain

Professor Dennis D.M. O’Leary,    Vincent J. Coates Chair in Molecular Neurobiology, Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, CA, USA

Professor Franck Polleux,    The Scripps Research Institute, Dorris Neuroscience Center, La Jolla, CA, USA

Dr David H. Rowitch,    University of California, San Francisco, CA, USA

Dr Gordon M. Shepherd,    Department of Neurobiology, Yale School of Medicine, New Haven, CT, USA

Professor Helen Tager‐Flusberg,    Department of Psychology and Department of Anatomy & Neurobiology, Boston University, Boston, MA, USA

Contributors

K. Akassoglou,    University of California, San Francisco, CA, USA

W.A. Alaynick,    Howard Hughes Medical Institute, La Jolla, CA, USA, Salk Institute for Biological Studies, La Jolla, CA, USA

A. Alunni,    Institute of Neurobiology Alfred Fessard, France

A. Alvarez-Buylla,    University of California, San Francisco, CA, USA

S.-L. Ang,    National Institute for Medical Research, London, England, UK

B. Appel,    University of Colorado School of Medicine, Aurora, CO, USA

P. Arlotta,    Harvard University, Cambridge, MA, USA, Harvard Medical School, Boston, MA, USA, Massachusetts General Hospital, Boston, MA, USA

E. Azim,    Harvard University, Cambridge, MA, USA, Harvard Medical School, Boston, MA, USA, Massachusetts General Hospital, Boston, MA, USA

R.J. Balice-Gordon,    University of Pennsylvania, Philadelphia, PA, USA

L. Bally-Cuif,    Institute of Neurobiology Alfred Fessard, France

R. Batista-Brito,    New York University School of Medicine, New York, NY, USA

M. Baumgardt,    Linköping University, Linköping, Sweden

J. Begbie,    University of Oxford, Oxford, UK

J. Benito-Sipos,    Universidad Autónoma de Madrid, Madrid, Spain

D.E. Bergles,    Johns Hopkins School of Medicine, Baltimore, MD, USA

K. Brennand,    Salk Institute for Biological Studies, La Jolla, CA, USA

J.J. Breunig,    Cedars-Sinai Medical Center, Los Angeles, CA, USA

N.L. Brown,    Cincinnati Children’s Research Foundation, Cincinnati, OH, USA, University of Cincinnati College of Medicine, Cincinnati, OH, USA

S.A. Buffington,    Baylor College of Medicine, Houston, TX, USA

K. Campbell,    Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA

A.E. Cardona,    The University of Texas at San Antonio, San Antonio, TX, USA

V.V. Chizhikov,    Seattle Children’s Hospital Research Institute, Seattle, WA, USA

M. Coolen,    Institute of Neurobiology Alfred Fessard, France

M. Crespo,    Weill Medical College of Cornell University, New York, NY, USA

A.M. Davies,    Cardiff School of Biosciences, Wales, UK

L.M. De Biase,    Johns Hopkins School of Medicine, Baltimore, MD, USA

B. Deneen,    Baylor College of Medicine, Houston, TX, USA

J.K. Fahrion,    Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

R.M. Fame,    Harvard University, Cambridge, MA, USA, Harvard Medical School, Boston, MA, USA, Massachusetts General Hospital, Boston, MA, USA

G. Fishell,    New York University School of Medicine, New York, NY, USA

I. Foucher,    Institute of Neurobiology Alfred Fessard, France

M.R. Freeman,    University of Massachusetts Medical School, Worcester, MA, USA

L. Fuentealba,    University of California, San Francisco, CA, USA

F. Gage,    Salk Institute for Biological Studies, La Jolla, CA, USA

A. Gauthier-Fisher,    Hospital for Sick Children, Toronto, ON, Canada

W.D. Gifford,    Howard Hughes Medical Institute, La Jolla, CA, USA, Salk Institute for Biological Studies, La Jolla, CA, USA

A. Grande,    Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

E.A. Grove,    University of Chicago, Chicago, IL, USA

M. Hayashi,    Howard Hughes Medical Institute, La Jolla, CA, USA, Salk Institute for Biological Studies, La Jolla, CA, USA

C.R. Hayworth,    University of Pennsylvania, Philadelphia, PA, USA

J. Hébert,    Albert Einstein College of Medicine, New York, NY, USA

A. Hemmati-Brivanlou,    The Rockfeller University, New York, NY, USA

O. Hobert,    Howard Hughes Medical Institute, Columbia University Medical Center, New York, NY, USA

C. Hochstim,    University of Southern California, Los Angeles, CA, USA

R.B. Hufnagel,    Cincinnati Children’s Research Foundation, Cincinnati, OH, USA, University of Cincinnati College of Medicine, Cincinnati, OH, USA

K.R. Jessen,    University College London, London, UK

J.E. Johnson,    University of Texas Southwestern Medical Center, Dallas, TX, USA

M. Kerschensteiner,    Ludwig-Maximilians Universität München, Munich, Germany

C. Kintner,    The Salk Institute for Biological Studies, La Jolla, CA, USA

H. Komuro,    Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

Y. Komuro,    Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

A. Kriegstein,    University of California, San Francisco, CA, USA

P.A. Kuert,    University of Basel, Basel, Switzerland

T. Kumada,    Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

H.C. Lai,    University of Texas Southwestern Medical Center, Dallas, TX, USA

B. Lamb,    Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

Y. Littner,    Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

J.L. MacDonald,    Harvard University, Cambridge, MA, USA, Harvard Medical School, Boston, MA, USA, Massachusetts General Hospital, Boston, MA, USA

J.D. Macklis,    Harvard University, Cambridge, MA, USA, Harvard Medical School, Boston, MA, USA, Massachusetts General Hospital, Boston, MA, USA

S. Martinez,    CSIC-Miguel Hernandez University, Alicante, Spain

M. Matise,    UMDNJ/Robert Wood Johnson Medical School, Piscataway, NJ, USA

D. Meijer,    Erasmus University Medical Center, Rotterdam, The Netherlands

D.M. Meredith,    University of Texas Southwestern Medical Center, Dallas, TX, USA

F. Merkle,    Harvard University, Cambridge, MA, USA

A. Meunier,    Institut National de la Santé et de la Recherche Médicale U1024, Paris, France, Centre National de la Recherche Scientifique UMR8197, Paris, France, Institut de Biologie de l’Ecole Normale Supérieuse (IBENS), Paris, France

K.J. Millen,    Seattle Children’s Hospital Research Institute, Seattle, WA, USA

R.H. Miller,    Case Western Reserve University, Cleveland, OH, USA

F.D. Miller,    Hospital for Sick Children, Toronto, ON, Canada

R. Mirsky,    University College London, London, UK

T. Misgeld,    Technische Universität München, Munich, Germany

A.V. Molofsky,    University of California, San Francisco, CA, USA

B.J. Molyneaux,    Harvard University, Cambridge, MA, USA, Harvard Medical School, Boston, MA, USA, Massachusetts General Hospital, Boston, MA, USA

E.S. Monuki,    University of California Irvine, Irvine, CA, USA

M. Nakafuku,    Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

H. Nakamura,    Tohoku University, Sendai, Japan

K.-A. Nave,    Max-Planck-Institute of Experimental Medicine, Göttingen, Germany

B.R. Nelson,    Seattle Children’s Research Institute, Seattle, WA, USA, University of Washington, Seattle, WA, USA

C. Nelson,    Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

I. Nikić,    EMBL Heidelberg, Heidelberg, Germany

N. Ohno,    Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

D.D.M. O’Leary,    The Salk Institute, La Jolla, CA, USA

S.L. Pfaff,    Howard Hughes Medical Institute, La Jolla, CA, USA, Salk Institute for Biological Studies, La Jolla, CA, USA

S.J. Pleasure,    University of California, San Francisco, CA, USA

L. Puelles,    University of Murcia, Murcia, Spain

R.M. Ransohoff,    Cleveland Clinic, Cleveland, OH, USA

M.N. Rasband,    Baylor College of Medicine, Houston, TX, USA

H. Reichert,    University of Basel, Basel, Switzerland

M.E. Ross,    Weill Medical College of Cornell University, New York, NY, USA

D. Rowitch,    University of California, San Francisco, CA, USA

J.L.R. Rubenstein,    University of California at San Francisco, San Francisco, CA, USA

K. Sawamoto,    Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

M.H. Schwab,    Max-Planck-Institute of Experimental Medicine, Göttingen, Germany

M.W. Sereda,    Max-Planck-Institute of Experimental Medicine, Göttingen, Germany, University of Göttingen, Göttingen, Germany

K. Sharma,    University of Chicago, Chicago, IL, USA

Q. Shen,    Tsinghua University, Beijing, China

S.J. Shnider,    Harvard University, Cambridge, MA, USA, Harvard Medical School, Boston, MA, USA, Massachusetts General Hospital, Boston, MA, USA

J.A. Siegenthaler,    University of California, San Francisco, CA, USA

L. Sommer,    University of Zurich, Zurich, Switzerland

N. Spassky,    Institut National de la Santé et de la Recherche Médicale U1024, Paris, France, Centre National de la Recherche Scientifique UMR8197, Paris, France, Institut de Biologie de l’Ecole Normale Supérieuse (IBENS), Paris, France

M. Sternfeld,    Howard Hughes Medical Institute, La Jolla, CA, USA, Salk Institute for Biological Studies, La Jolla, CA, USA

A.M. Stocker,    The Salk Institute, La Jolla, CA, USA

T. Stork,    University of Massachusetts Medical School, Worcester, MA, USA

S.R.W. Stott,    National Institute for Medical Research, London, England, UK

J. Svaren,    University of Wisconsin-Madison, Madison, WI, USA

S. Temple,    Neural Stem Cell Institute, Rensselaer, NY, USA

S. Thor,    Linköping University, Linköping, Sweden

S. Tole,    Tata Institute of Fundamental Research, Mumbai, India

J. Tsai,    Howard Hughes Medical Institute, La Jolla, CA, USA, Salk Institute for Biological Studies, La Jolla, CA, USA

M. Wegner,    Universität Erlangen-Nürnberg, Erlangen, Germany

A. Zembrzycki,    The Salk Institute, La Jolla, CA, USA

Introduction to Comprehensive Developmental Neuroscience

It is broadly accepted that understanding the genetic, molecular, and cellular mechanisms of neural development is essential for understanding evolution and disorders of neural systems. Recent advances in genetic, molecular, and cell biological methods have generated a massive increase in new information. By contrast, there is a paucity of comprehensive and up-to-date syntheses, references, and historical perspectives on this important subject. Therefore, we embarked on the formidable task of assembling a novel resource entitled ‘Comprehensive Developmental Neuroscience.’ We hope that the books in this series will serve as valuable references for basic and translational neuroscientists, clinicians, and students.

To help with this enormous task, we invited leading experts in various subfields to select the subjects and invite appropriate authors. We were gratified by the number of busy scientists who accepted the invitation to write their articles. All the chapters have been peer reviewed by the Section Editors to ensure accuracy, thoroughness, and scholarship.

In the resulting three volumes, we cover a broad array of subjects on neural development. We organized the volumes chronologically according to the ordered steps in neural development. In addition, each volume is subdivided into three to four sections, each edited by world experts in these areas. The sections have 10–20 chapters that are written and illustrated by leading scientists.

This volume has 48 chapters devoted mainly to patterning and cell type specification in the developing central and peripheral nervous systems (CNS and PNS). This volume is subdivided into three sections. The first is on the mechanisms that control regional specification, which generate subdivisions of the nervous system. The second is on mechanisms that regulate the proliferation of neuronal progenitors and that control differentiation and survival of specific neuronal subtypes. The third section addresses the mechanisms controlling development of non-neural cells: astrocytes, oligodendroyctes, Schwann cells, microglia, meninges, blood vessels, ependyma, and choroid plexus.

Volume 2 in the series has 56 chapters devoted to migration (cell and axonal), the formation of neuronal connections, and the maturation of neural functions. This volume is subdivided into four sections. The first is on mechanisms that control the formation of axons and dendrites. The second is on the mechanisms that regulate cell migration that disperses specific subtypes of cells along highly defined pathways to specific destinations. The third section is on the regulation of synapse formation and maintenance during development; in addition, it has chapters on synaptogenesis in the mature nervous system in response to neurogenesis, neural activity, and neural trauma. The final section is on the developmental sequences that regulate neural activity, from cell-intrinsic maturation to early correlated patterns of activity.

Volume 3 in the series has 40 chapters devoted to the anatomical and functional development of neural circuits and neural systems, as well as chapters that address neurodevelopmental disorders in humans and experimental organisms. This volume is subdivided into three sections. The first is on the mechanisms that control the assembly of neural circuits in specific regions of the nervous system, and as a function of neural activity and critical periods. The second section concentrates on multiple aspects of cognitive development, particularly in humans. The final section addresses disorders of the nervous system that arise through defects in neural development, building on the principles that are addressed in earlier sections of the book.

John L.R. Rubenstein and Pasko Rakic

I

Induction and Patterning of the CNS and PNS

Chapter 1 Telencephalon Patterning

Chapter 2 Morphogens, Patterning Centers, and their Mechanisms of Action

Chapter 3 Midbrain Patterning

Chapter 4 Area Patterning of the Mammalian Cortex

Chapter 5 The Formation and Maturation of Neuromuscular Junctions

Chapter 6 Neural Induction of Embryonic Stem/Induced Pluripotent Stem Cells

Chapter 7 Spinal Cord Patterning

Chapter 8 Patterning of the Diencephalon

Chapter 9 Neural Induction Embryonic Stem Cells

Chapter 10 Plan of the Developing Vertebrate Nervous System

Chapter 11 Cerebellar Patterning

Chapter 12 Hox Genes and Neural Patterning in Drosophila

Chapter 13 Induction and Patterning of Neural Crest and Ectodermal Placodes and their Derivatives

Chapter 1

Telencephalon Patterning

S. Tole¹ and J. Hébert²,    ¹Tata Institute of Fundamental Research, Mumbai, India, ²Albert Einstein College of Medicine, New York, NY, USA

Outline

1.1 Introduction

1.2 Telencephalon Induction

1.2.1 The Anterior Neural Ridge

1.2.2 FGF Signaling

1.2.3 Wnt Antagonism

1.2.4 Interactions of Low Wnt with FGFs and BMPs

1.3 Overview of Early Telencephalic Subdivisions

1.4 Establishing Dorsal Versus Ventral Domains

1.4.1 Shh and Gli3, Two Key Players

1.4.2 Foxg1 and FGFs Cooperatively Promote Ventral Development

1.4.3 Establishing the Dorsal Telencephalic Domain

1.4.4 Sharpening the Dorsal–Ventral Border

1.4.5 The Olfactory Bulbs

1.5 Boundary Structures as Organizing Centers and CR Cell Sources

1.5.1 Nomenclature of Domains in the Early Telencephalic Neuroepithelium

1.5.2 Specification of the Hem and the Antihem

1.5.2.1 Molecular Mechanisms that Act to Position and Specify the Cortical Hem

1.5.2.2 Molecular Mechanisms that Act to Specify and Position the Antihem

1.5.3 CR Cells Arise from Four Telencephalic Boundary Structures

1.5.4 Organizer Functions of Telencephalic Boundary Structures

1.5.4.1 Rostral Signaling Center/Septum

1.5.4.2 Hem

1.5.4.3 Antihem

1.6 Subdividing Ventral Domains

1.6.1 The Striatum and Pallidum

1.6.2 The Amygdala

1.6.3 An Evolutionary Perspective for How the Neocortex Arose?

1.6.4 Lineage and Fate Mapping in the Ventral Telencephalon

1.7 Conclusions

Acknowledgments

References

1.1 Introduction

The neural networks of the adult cerebral hemispheres, which are one of the most complex structures known to us, underlie the vast range of human behaviors. Despite this complexity, the cerebral hemispheres start off during embryonic development as a simple sheet of neuroepithelial cells. This neuroepithelium constitutes the nascent telencephalon, located toward the anterior end of the neural plate. As development proceeds, the telencephalic neuroepithelium becomes patterned into distinct progenitor regions, which later give rise to specific neuronal subtypes, a process that is essential for the proper wiring of the cerebrum. Defects in these early patterning processes, even subtle ones, can result in serious intellectual and behavioral deficits.

Here, how the neuroepithelium at the anterior end of the neural plate is specified to become the telencephalon is discussed. Also, the mechanisms that pattern the telencephalic neuroepithelium into the discrete progenitor domains destined to generate specific neuron subtypes are reviewed. Finally, what is known about the migration of neuroblasts from several progenitor domains and how this results in distinct combinations of neurons in each functionally different telencephalic area are examined.

A molecular framework is emerging that explains how the fates of precursor cells located in different areas within the telencephalic neuroepithelium and at different developmental stages are regulated. An interplay between cell extrinsic factors secreted from signaling centers and cell intrinsic factors in the neuroepithelium is central to the regulation of the rates of cell proliferation, differentiation, and apoptosis of telencephalic precursors and the types of neurons that they generate. Not surprisingly, as in most developing tissues throughout the body, the cell extrinsic factors include members of the fibroblast growth factor (FGF), bone morphogenetic protein (BMP), and Wnt families as well as Sonic hedgehog (SHH). However, the cell intrinsic factors, which are thus far mostly transcription factors, are more specific to the developing anterior nervous system and include factors encoded by genes such as Foxg1, Gli3, Pax6, Lhx2, Gsx2 (Gsh2), Nkx2.1, and Emx2. This chapter attempts to describe the critical genetic interactions that link extrinsic and intrinsic factors in telencephalon patterning.

1.2 Telencephalon Induction

1.2.1 The Anterior Neural Ridge

The initial formation of the telencephalon shares features with the induction of other tissues, such as the limbs, branchial arches, and mid-hindbrain. Most notably, in each case, there is a discrete group of adjacent cells that acts as an organizer to induce the formation of these tissues. For the telencephalon, the inducing cells are those of the anterior neural ridge (ANR; found in mice) or anterior neural border (found in zebrafish; for simplicity, ANR is used henceforth). The ANR is located at the anterior end of the embryo and comprises the edge between the neurectoderm and the underlying ectoderm. Cells at the rostrolateral end of the neural plate are fated to become the telencephalon (Cobos et al., 2001; Eagleson et al., 1995; Inoue et al., 2000). These cells turn on expression of Foxg1, a transcription factor gene of the forkhead family. RNA in situ hybridization analysis and lineage tracing using Foxg1Cre mice have shown that Foxg1 expression in the anterior neuroepithelium specifically marks telencephalic precursor cells and delineates most of the embryonic telencephalon (Hébert and McConnell, 2000; Shimamura and Rubenstein, 1997; Shimamura et al., 1995; Tao and Lai, 1992). In cultured explants of mice, if the ANR is dissected away from the anterior neuroepithelium, expression of Foxg1 fails to be induced (Shimamura and Rubenstein, 1997). Similarly, removal of ANR cells in zebrafish results in a failure to induce the normal expression of other telencephalic markers, Emx1 and Dlx2, two transcription factor genes expressed in presumptive dorsal and ventral telencephalic domains, respectively (Houart et al., 1998). Conversely, if the ANR is transplanted to more caudal regions of the neural plate, it induces ectopic expression of Emx1, Dlx2, and Foxg1 (Houart et al., 1998, 2002). Taken together, these studies suggest that the ANR is necessary and sufficient to induce telencephalic character in the adjacent anterior neural plate.

1.2.2 FGF Signaling

Telencephalon induction also shares molecular mechanisms with other tissues. For several parts of the embryo, including the limbs and mid-hindbrain, the induction of the tissue by an organizer seems to be mediated in part by FGFs. FGF-soaked beads placed ectopically in the presumptive diencephalic region or flank of chick embryos induce ectopic midbrains and limbs, respectively, whereas deletion of Fgf8 in the inducing cells leads to loss of the midbrain and limbs (Chi et al., 2003; Cohn et al., 1995; Crossley et al., 1996a,b; Lewandoski et al., 2000). FGF genes, including Fgf8, also are expressed in the ANR, where they likely mediate organizer activity for the telencephalon (Figure 1.1). A bead soaked in FGF8 and placed on a cultured explant of anterior neural plate can induce Foxg1 expression (Shimamura and Rubenstein, 1997). Conversely, abolishing FGF signaling in the anterior neural plate by knocking out three FGF receptor genes, Fgfr1, Fgfr2, and Fgfr3, leads to loss of most or all Foxg1-expressing cells and a failure to form the telencephalon (Paek et al., 2009). This phenotype is not observed when any single FGF receptor gene or a pair of them is deleted, indicating that at the earliest stages of telencephalon development, Fgfr1, Fgfr2, and Fgfr3 can compensate for each other functionally (Gutin et al., 2006). The same is true for the ligands (Figure 1.2). Deletion of Fgf8 alone does not lead to loss of the telencephalon (Storm et al., 2006), indicating that other FGF ligand genes must be compensating for its loss (e.g., Theil et al., 2008). Consistent with this possibility, four other FGF ligand genes, Fgf3, Fgf15, Fgf17, and Fgf18, are expressed at the anterior end of the developing neural tube (Crossley and Martin, 1995; Maruoka et al., 1998; McWhirter et al., 1997; Shinya et al., 2001).

Figure 1.1 An early somite stage mouse embryo is used to illustrate two key factors at work in inducing the telencephalon. (a) Whole embryo showing the plane of section of the schematic in (b). Low Wnt signaling (yellow) along with FGFs (green) induces cells in the anterior–lateral neural plate to adopt a telencephalic fate (blue).

Figure 1.2 Illustration of the central role of FGFs in telencephalon formation. FGFs induce cells to adopt a telencephalic fate at the neural plate stage, but the effects of reducing FGF signaling in the anterior neural plate are better depicted later, as in the midgestation (E12.5) mouse telencephalon (a). With decreasing FGF signaling, there is a progressive loss of telencephalic tissue starting with anterior–ventral–medial areas progressing to posterior–dorsal–lateral ones ((b) coronal views; (c) sagittal views). Only the most dorsomedial area (choroid plexus and cortical hem) is spared. See text for details.

Although it is clear that FGFs play a central role in the earliest steps of telencephalon formation, it has not been strictly demonstrated that they mediate classic organizer activity at this stage. Spemann and Mangold (1924) defined an organizer as a group of cells that has the potential to ectopically induce neighboring cells to form a normally structured tissue, usually with mirror-image symmetry to the normal tissue, as was the case in their experiments with tadpole body axis duplication and as is the case with midbrain duplication due to a bead of FGF8 placed in the presumptive diencephalic region (Crossley et al., 1996a). For telencephalon induction, this experiment would be technically difficult to execute in the mouse, although perhaps possible in the chick. Nevertheless, evidence discussed in the Rostral signaling center/septum subsection supports a role for FGFs as mediators of organizer activity in the telencephalon. What remains almost entirely unresolved is how FGF activity itself translates into the complex unfolding of telencephalon growth and patterning.

The regulation of cell survival is likely to play some role. If either the ANR is ablated or FGF signaling is abolished in the anterior neural plate, all or most telencephalic precursor cells undergo apoptosis (Houart et al., 1998; Paek et al., 2009), similar to what occurs in limb and mid-hindbrain precursors, for example, when Fgf8 is deleted. Why the cells die in the absence of FGF signaling is not understood. The answer may come from elucidating how the expression of genes that control cell survival and proliferation is regulated. For example, in glioblastoma cells and perhaps forebrain neuroepithelial cells, the cytostatic/proapoptotic gene Cdkn1a (p21Cip1) is directly regulated in its promoter region by intracellular mediators of both cytostatic and mitogenic factors (Seoane et al., 2004). The Cdkn1a promoter contains an activation element to which binds a FoxO/SMAD complex and a repressor element to which binds a cMYC/MIZ complex. In proliferating cells, Cdkn1a is repressed by cMyc/Miz (presumably in response to mitogenic factors). In response to TGFβ signals, however, SMADs inhibit cMyc and form a complex with FoxO to activate Cdkn1a expression (Seoane et al., 2004).

Remarkably, FoxG1 competes with the FoxO/SMAD complex for binding to its cis element in the Cdkn1a promoter. Whereas FoxO/SMAD binding promotes Cdkn1a expression, FoxG1 represses it (Seoane et al., 2004). FGFs and FoxG1 positively regulate each other’s expression (Martynoga et al., 2005; Paek et al., 2009; Shimamura and Rubenstein, 1997; Storm et al., 2003). Thus, when FGF signaling is abolished and Foxg1 is turned off, the expression of cytostatic/proapoptotic genes such as Cdkn1a may be derepressed in the anterior neural plate, leading to cell death. It remains to be seen if Cdkn1a itself and/or other genes with related functions are regulated by FGFs and other extracellular signals to control the survival and proliferation of anterior neural plate cells as they are induced to become telencephalic.

1.2.3 Wnt Antagonism

At least in zebrafish, FGFs are not the only factors released from the ANR that induce anterior neural plate cells to adopt a telencephalic fate. A secreted frizzled-related Wnt antagonist, Tlc, that is expressed in the ANR is necessary and sufficient to induce the telencephalon (Houart et al., 2002). Antisense morpholinos against tlc lead to a loss of the telencephalon, and conversely tlc-expressing cells can rescue the loss of telencephalon and cell death in ANR-ablated embryos (Houart et al., 2002). Moreover, tlc-expressing cells can induce ectopic expression of emx1 and foxg1 in more posterior neural tissue. Tlc likely acts by inhibiting Wnts as expected since transplanting Wnt-expressing cells into the ANR inhibits expression of telencephalic genes (Houart et al., 2002).

Consistent with the idea that inhibiting Wnts is necessary to induce the telencephalon, zebrafish embryos mutant for the masterblind gene, which encodes Axin, a negative regulator of Wnt signaling, lack a telencephalon (Heisenberg et al., 2001; Masai et al., 1997; van de Water et al., 2001). Mouse embryos that are mutant for Six3, a direct repressor of certain Wnt genes, also lack a telencephalon, suggesting that Wnt antagonism is a conserved mechanism of telencephalon induction (Lagutin et al., 2003). However, Six3 is also required to promote Shh expression and ventral development of not only the telencephalon but also the rest of the forebrain (Geng et al., 2008). It also remains unclear if secreted frizzled-related proteins emanate from the ANR to specify the telencephalon in species other than zebrafish.

The source of the Wnts that are antagonized in telencephalon induction is unclear. The requirement for low Wnt signaling in forming the telencephalon may reflect a continuation of the earlier low-anterior to high-posterior Wnt gradient involved in anterior–posterior patterning of the neural plate, which has been well characterized across several species (Wilson and Houart, 2004) and which is discussed in the accompanying chapters on early neural patterning. Alternatively, a Wnt source internal to the anterior neural plate may play a role, perhaps the cortical hem primordium, which may be specified very early prior to neural tube closure.

1.2.4 Interactions of Low Wnt with FGFs and BMPs

Low levels of Wnt signaling appear necessary to promote appropriate levels of FGF gene expression in the anterior tip of the embryo. Tlc is both necessary and sufficient to promote fgf8 expression in anterior neural tissue of the zebrafish embryo (Houart et al., 2002). In embryos in which the ANR is ablated, tlc-expressing cells rescue not only fgf8 expression but also cell survival (Houart et al., 2002). Hence, the evidence to date indicates that low Wnt signaling acts upstream of FGFs in telencephalon induction, although it remains possible that FGFs also restrict Wnt signaling in a negative feedback loop. Other factors are also likely to be critical to telencephalon induction. For example, extracellular matrix components are probably required to set up gradients for Wnts and FGFs and potentiate their activities, as well as intracellular mediators of these signaling pathways. However, only the surface has been scratched.

How the ANR itself is formed is also a poorly understood process. BMP signaling is likely to play an important role. In bmp2b mutant zebrafish embryos, despite an expansion of the neural plate at the expense of ectoderm, the telencephalon fails to form (Barth et al., 1999). Moreover, expression of tlc at the anterior tip of the embryo is lost when an exogenous BMP inhibitor, Noggin, is added (Houart et al., 2002). These results together suggest that tlc expression and perhaps the ANR itself are likely to be induced by a threshold level of BMPs, which emanate from the surrounding ectoderm.

1.3 Overview of Early Telencephalic Subdivisions

Once the anterior neural plate acquires a telencephalic fate and expresses Foxg1, it becomes further subdivided into domains distinguishable by the expression of molecular markers. These include genes encoding transcription factors that are expressed in specific telencephalic subdomains, such as Nkx2.1, Gsx2, Pax6, and Emx2, as well as extracellular factors that are expressed in signaling centers at the edges of these subdomains, such as Shh, Fgfs, Wnts, and Bmps. In most or all cases, not only do these genes serve as useful markers, but their functions are also essential in patterning the telencephalic neuroepithelium, as discussed in this chapter. Prior to neural tube closure, two broad ventral and dorsal domains can already be distinguished molecularly. These roughly prefigure the dorsal neuroepithelium that primarily generates glutamatergic neurons and the ventral one that primarily generates GABAergic neurons (Figure 1.3).

Figure 1.3 Schematic of a midgestational mouse head depicting the domains of progenitor cells that generate broad subtypes of neurons. Dorsal progenitors generate glutamatergic neurons and ventral progenitors GABAergic ones. Progenitors in areas between the hemispheres and between the dorsal–ventral areas give rise to the earliest born neurons, the Cajal–Retzius cells. ba, branchial arch; di, diencephalon; h, heart; mes, mesencephalon; np, nasal pit; tel, telencephalon.

Shortly after neural tube closure, these two domains become further subdivided. The dorsal telencephalic domain (pallium) gets split into several regions. The largest of these gives rise to the neocortex, which then becomes patterned into different functional areas as described in a separate chapter. Specification of other cortical regions, such as the hippocampus located caudomedially, occurs as a result of the action of neighboring signaling centers. One of these signaling centers, the cortical hem, not only acts as an organizer for the hippocampus but also generates some of the earliest born telencephalic neurons, the Cajal–Retzius cells (CR; Meyer et al., 2002; Takiguchi-Hayashi et al., 2004; Yoshida et al., 2006). Progenitors at the border between the ventral and dorsal telencephalon and those at the rostromedial end also contribute CR cells to the telencephalon, as discussed below. The olfactory bulb (OB) located at the anterior tip of the telencephalon is also considered a dorsal derivative.

The ventral telencephalic domain (subpallium) can be divided into two early regions: a medial part designated as the medial ganglionic eminence (MGE) and a posterior–lateral part that forms the lateral and caudal ganglionic eminences (LGE and CGE). Each ventral region generates specific GABAergic populations of neurons that either come to reside in the basal ganglia and associated limbic structures, including the amygdala and nucleus accumbens, or migrate long distances to populate all areas of the cortex. The MGE produces somatostatin, parvalbumin, and some neuropeptide Y-expressing interneurons that populate the basal ganglia and cortex; the CGE produces a diversity of interneurons, including calretinin/vasoactive intestinal peptide-expressing and Reelin-expressing ones; the LGE produces a large fraction of the OB interneurons, as well as GABAergic projection neurons that reside in several ventral areas including the striatum and limbic structures (Miyoshi et al., 2010; Nery et al., 2002; Wichterle et al., 2001; Wonders and Anderson, 2006). The partitioning of the telencephalic neuroepithelium into functionally different dorsal and ventral domains is due to the effect of secreted factors emanating from signaling centers, as discussed below.

1.4 Establishing Dorsal Versus Ventral Domains

1.4.1 Shh and Gli3, Two Key Players

Although the mechanisms that divide the early telencephalic neuroepithelium into presumptive dorsal and ventral domains remain superficially understood, key players have been identified (Figure 1.4). These include both cell-intrinsic and -extrinsic factors. Two of these factors are GLI3, a zinc finger transcription factor that acts to dorsalize the telencephalon, and SHH, a secreted signaling protein that acts to ventralize the telencephalon. The Gli3 gene, which was first identified as the classical mouse mutation Extra toes (Hui and Joyner, 1993), is initially expressed throughout the telencephalic neuroepithelium before becoming progressively restricted to the dorsal domain (Aoto et al., 2002; Corbin et al., 2003). In the Gli3 mouse mutant, the dorsal telencephalon fails to develop normally. The caudomedial areas, including the choroid plexus, cortical hem, and hippocampus, fail to form, and the neocortical area is progressively lost (Figure 1.4; Grove et al., 1998; Kuschel et al., 2003; Theil et al., 1999; Tole et al., 2000).

Figure 1.4 Early model for the establishment of dorsal–ventral telencephalic domains. (a) Rough representation of the early expression patterns of key factors in the developing telencephalon from the neural plate stage (dorsal view), to the early neural tube stage (cross-section), to a stage that corresponds to midgestation (preneurogenesis) in the mouse. (b) Salient interactions between these factors, as well as FGFs and Foxg1, are presented (see text for details). Lhx2, a key early player in establishing the dorsal domain, is discussed in a separate section on the hem and antihem.

The Shh gene is expressed in the midline of the neural plate and continues to be expressed in the ventral midline after neural tube closure (Echelard et al., 1993). In Shh−/− mouse embryos, all ventral telencephalic precursors are missing as assessed by loss of expression of ventral markers including Dlx2, Gsx2, and Nkx2.1 (Chiang et al., 1996; Fuccillo et al., 2004; Ohkubo et al., 2002; Rallu et al., 2002; Rash and Grove, 2007). Conversely, ectopic expression of Shh induces these ventral markers in the dorsal telencephalon of zebrafish and mice (Barth and Wilson, 1995; Ericson et al., 1995; Hauptmann and Gerster, 1996; Kohtz et al., 1998; Shimamura and Rubenstein, 1997). In addition to a lack of ventral cell types, the telencephalon of Shh−/− mutants is severely reduced in size because of its requirement in maintaining cell proliferation and survival (Ericson et al., 1995; Litingtung and Chiang, 2000; Ohkubo et al., 2002; Rowitch et al., 1999). Hence, it remains unclear what the relative contributions of cell death, reduced proliferation, and cell fate transformation are to the loss of ventral precursor cells in the Shh mutant. Along with SHH itself, a range of factors required for SHH activity are also needed to generate ventral telencephalic precursors (e.g., factors involved in SHH protein processing, Huang et al., 2007; ciliogenesis, Ashique et al., 2009; or factors that genetically interact such as E2f4, Ruzhynsky et al., 2007).

Mutations of Shh in both mice and humans lead to holoprosencephaly (Chiang et al., 1996; Roessler et al., 1996), a disorder in which medial areas of both forebrain and craniofacial tissues do not develop normally, leading to the incomplete separation of bilaterally symmetrical structures including the telencephalic hemispheres. The morphological defects within the telencephalon in Shh mutants in both mice and humans appear to extend beyond the ventral regions into the dorsal telencephalon in that the nascent hemispheres fail to separate dorsally (Chiang et al., 1996; Ohkubo et al., 2002; Solomon et al., 2010). However, this is not due to a failure of dorsomedial cell types to initially be generated, because they can still be identified in the Shh mutant, but perhaps due instead to a lack of overall growth and expansion of the hemispheres (Fernandes et al., 2007; Hayhurst et al., 2008; Rash and Grove, 2007). Moreover, humans carrying a Shh mutation rarely, if ever, show a variant of holoprosencephaly (midline interhemispheric holoprosencephaly (MIH)) in which the dorsal areas are affected (Solomon et al., 2010).

Remarkably, in double mutants lacking both Shh and Gli3, early ventral patterning is by and large rescued (Aoto et al., 2002; Rallu et al., 2002; Rash and Grove, 2007). Therefore, Shh controls the relative size of the dorsal and ventral domains of the telencephalon in large part by restricting the dorsalizing function of Gli3. In this way, rather than directly promoting ventral cell fates, Shh functions early on to promote ventral identity by preventing dorsalization. The rescue of early ventral development in the Shh mutant by elimination of Gli3 implies that other factors function independently or downstream of Shh to generate ventral precursor cells (Rallu et al., 2002).

1.4.2 Foxg1 and FGFs Cooperatively Promote Ventral Development

Foxg1 and Fgfs are both required for generating ventral precursors independent of Shh. The knockout of Foxg1 in mice or morpholino knockdown in zebrafish results in the loss of ventral precursor cells (Danesin et al., 2009; Dou et al., 1999; Martynoga et al., 2005; Xuan et al., 1995). Unlike the Shh−/− phenotype, however, in the Foxg1−/− mutants ventral cells are not rescued by removal of Gli3 (Hanashima et al., 2007), suggesting that Foxg1 acts genetically downstream of Shh and Gli3. Consistent with this interpretation, in zebrafish, shh misexpression cannot rescue ventral development in the foxg1 knockdowns, whereas foxg1 can partially rescue ventral cells in embryos in which SHH signaling is blocked (Danesin et al., 2009). Notably, the telencephalon is entirely lost in the Foxg1;Gli3 mouse double mutant, indicating that Gli3 and Foxg1 are essential for generating the dorsal and ventral subdivisions of the telencephalon, respectively (Hanashima et al., 2007).

Fgfs are also required for generating ventral telencephalic cells. In zebrafish, without fgf8 and fgf3 the ventral telencephalon does not form (Shanmugalingam et al., 2000; Shinya et al., 2001; Walshe and Mason, 2003). In mouse, ventral cells fail to be generated in Fgfr1−/−;Fgfr2−/− double mutants and Fgf8 hypomorphic and null mutants (Gutin et al., 2006; Storm et al., 2006). FGFs induce all ventral regions independently of Shh, because even when Shh is expressed and active, no ventral structures develop if Fgfr1 and Fgfr2 are disrupted (Gutin et al., 2006). Moreover, FGF8-soaked beads ectopically induce expression of ventral markers in the dorsal telencephalon, even in the absence of SHH signaling (Kuschel et al., 2003), and electroporation of an Fgf8-expressing construct can rescue expression of ventromedial genes in Shh−/− mutants (Okada et al., 2008). As for the Foxg1 mutant and unlike for the Shh mutant, the loss of Gli3 does not rescue the loss of ventral cells in the Fgfr1; Fgfr2 mutant, placing FGFs genetically downstream of Gli3 (Gutin et al., 2006).

In mice, Foxg1 and Fgfs promote each other’s expression in the nascent telencephalon, forming a positive feedback loop that promotes ventral development. In Foxg1−/− mutants, Fgf8 expression is lost (Martynoga et al., 2005). Conversely, FGF signaling is both necessary and sufficient to promote Foxg1 expression: FGF8-soaked beads induce expression of Foxg1 in cultured telencephalic explants (Shimamura and Rubenstein, 1997), and Foxg1 expression is reduced in Fgf8 mutants and almost absent in the Fgfr1−/−; Fgfr2−/−; Fgfr3−/− triple mutant (Paek et al., 2009; Storm et al., 2006).

In addition, although Shh is required to maintain normal expression levels of both Foxg1 and Fgf genes, it does so indirectly. The reduction in Foxg1 expression observed in Shh−/− mouse mutants is due to the gain of GLI3-repressor activity because in Shh−/−;Gli3−/− double mutants Foxg1 expression recovers despite the absence of Shh (Rash and Grove, 2007). The maintenance of Fgf expression by Shh is also accomplished indirectly via repression of GLI3. Shh is required to promote and maintain the expression of Fgf3, Fgf8, Fgf15, Fgf17, and Fgf18 in the anterior medial telencephalon (Aoto et al., 2002; Ohkubo et al., 2002; Rash and Grove, 2007). In the Shh−/−;Gli3−/− mutant, however, Fgf expression is recovered because it is no longer repressed by GLI3. Moreover, the fact that Fgf expression is similarly expanded in both the Gli3−/− and Shh−/−;Gli3−/− mutants confirms that Shh promotes Fgf expression only indirectly by repressing GLI3 function (Aoto et al., 2002; Kuschel et al., 2003; Rash and Grove, 2007; Theil et al., 1999). Overall, these studies suggest that ventral telencephalic cells are lost in the Shh−/− mutant because of the unchecked action of the GLI3-repressor, which results in loss of Fgf expression and reduced Foxg1 expression.

1.4.3 Establishing the Dorsal Telencephalic Domain

Although Foxg1 and Fgfs are absolutely required for generating the ventral telencephalon, they also participate in forming the dorsal telencephalon. As discussed above, when FGF signaling is completely abolished by knocking out three FGF receptor genes in the mouse, not only the ventral telencephalon but also the dorsal domain is missing (Paek et al., 2009). Similarly, in Foxg1−/− mutants, in addition to the lack of ventral cells, the dorsal area is reduced in size (Xuan et al., 1995), although this is less severe than with the complete loss of FGF signaling. Loss of dorsal cells in the Foxg−/− mutant is due in part to the premature differentiation of precursor cells into early-born neurons and in part to the loss of anterior–lateral precursor cells, as the remaining dorsal region appears to acquire medial–caudal features (Hanashima et al., 2004, 2007; Muzio and Mallamaci, 2005; Xuan et al., 1995). Notably, foxg1 has also been shown in zebrafish embryos to restrict dorsal development by directly repressing wnt8b expression (Danesin et al., 2009). However, whereas in Foxg1−/− mouse embryos Fgf8 expression is lost, in zebrafish embryos treated with foxg1 morpholinos fgf8 is upregulated (Danesin et al., 2009; Martynoga et al., 2005). This difference could be accounted for by either a difference in species or a dose-dependent effect of Foxg1, as a null mutation is used in the mouse whereas in zebrafish, foxg1 may still be expressed at a low level. Nevertheless, Foxg1 appears to have dual roles in the dorsal telencephalon: (1) expanding its size in conjunction with FGFs (mainly anterior–lateral regions) and (2) restricting posterior–medial cell fates by restricting Wnt expression.

Consistent with a role for Wnts in telencephalic dorsalization, Wnts appear necessary and sufficient, together with FGFs, to induce progressively more mature dorsal identities to telencephalic precursor cells in chick embryos (Gunhaga et al., 2003). In this process, Wnts appear to act through the canonical intracellular signaling pathway, because in mice, gain- and loss-of-function mutations in β-catenin, an intracellular effector of canonical Wnt signaling, lead to gain and loss of dorsal telencephalic cell identities, respectively (Backman et al., 2005). Wnts may not be the only factors emanating from the dorsomedial telencephalic area that promote dorsal identity. BMP4 and BMP5-soaked beads placed in the ventral forebrain of chick embryos disrupt the ventral identity of surrounding cells and loss of megalin in mice, which results in increased Bmp4 expression, leads to a loss of ventral precursors (Golden et al., 1999; Spoelgen et al., 2005). However, more direct evidence for a requirement for BMPs in specifying dorsal identity is still lacking. In fact, dorsal precursors appear to be specified normally in mouse mutants lacking both Bmpr1a and Bmpr1b, although functional compensation by a more distantly related Bmpr type I gene cannot be excluded (Fernandes et al., 2007). It is interesting to note that Wnts repress telencephalon induction early on (as discussed in the Telencephalic Induction section above), but later promote dorsal telencephalic identities. In both cases, however, Wnt signaling may be acting in a temporal continuum to keep Foxg1 expression in check: early on repressing it in caudal regions of the neural plate and later repressing it in the dorsomedial regions of the telencephalon itself.

1.4.4 Sharpening the Dorsal–Ventral Border

In inducing dorsal identity to telencephalic cells in chick embryos, Wnt3A maintains expression of Pax6 (Gunhaga et al., 2003). Pax6, a paired-box transcription factor gene, is the key to establishing dorsal identities. Moreover, Pax6 is essential in sharpening the border that sets the dorsal apart from the ventral telencephalon. Pax6 is first expressed throughout the neuroepithelium of the neural plate that is destined to form the telencephalon (Inoue et al., 2000). After neural tube closure,