Neocortical Neurogenesis in Development and Evolution E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1969

Veröffentlichungsjahr: 2023

Beschreibung

NEOCORTICAL NEUROGENESIS IN DEVELOPMENT AND EVOLUTION Understanding the development and evolution of the mammalian neocortex The development of the mammalian brain, including the human brain, is inextricably linked with its evolution. Of particular interest is the development of the neocortex, the youngest part of the cerebral cortex in evolutionary terms and the seat of such vital functions as sensory perception, generation of motor commands, and higher-order cognition. The process of neurogenesis is crucial to the formation and function of the neocortex, but this process is complex, based on species-specific adaptations of old and acquired new traits that subserve specific functions introduced during mammalian evolution. Neocortical Neurogenesis in Development and Evolution provides a groundbreaking and comprehensive overview of neurogenesis in the developing neocortex and its evolutionary implications. It covers the generation of neurons and their migration to their functional positions, neural patterning, cortical folding, and variations and malformations of cortical development. Readers will find: * A comprehensive review of the evolution and development of the neocortex in mammals -- the part of our brain involved in the higher cognitive functions * A multitude of subject disciplines ranging from neuroscience, molecular biology, genetics, developmental biology, evolutionary biology and medicine to provide a holistic understanding of the evolutionary youngest part of the cerebral cortex * Coverage of neurogenesis in the developing neocortex and how this contributes to our understanding of the evolutionary implications Neocortical Neurogenesis in Development and Evolution is essential for researchers and postgraduates in neuroscience, developmental biology, evolutionary biology, and medical research.

Leseprobe

Neocortical Neurogenesis in Development and Evolution

Edited by

Wieland B. Huttner Max Planck Institute of Molecular Cell Biology and Genetics Dresden, Germany

This edition first published 2023

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Hardback ISBN: 9781119860808; ePub ISBN: 9781119860822; ePDF ISBN: 9781119860815; Obook ISBN: 9781119860914

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To Gisela

Contents

Cover

Title Page

Copyright Page

Dedication

Foreword

Preface

Part 1 Cortical Progenitors and Germinal Zones

1 Neural Stem Cells as Glia

1.1 Introduction and Definitions

1.1.1 Neural Stem Cell Definition

1.1.2 Glial Cell Definition

1.2 Radial Glia as Neural Stem Cells

1.2.1 Neuronal Progeny and Multipotency

1.2.2 Cell Division and Self-renewal

1.2.3 Glial Aspects of Radial Glia

1.3 Heterogeneity of Apical Radial Glial Cells

1.3.1 Short Neural Precursors

1.3.2 Truncated Radial Glia

1.3.3 Subapical Radial Glia

1.4 Basal Radial Glial Cells and their Heterogeneity

1.5 Radial Glial Cells in Phylogeny

References

2 Diversity and Evolution of Human Cortical Progenitor Cell Types

2.1 Progenitor Cell Diversity

2.1.1 Neuroepithelial Cells

2.1.2 Ventricular Radial Glia Cells

2.1.3 Intermediate Progenitor Cells

2.1.4 Outer Radial Glia Cells

2.1.5 Systematically Defining Progenitor Cell Diversity

2.2 Progenitor Cell Evolution

2.2.1 Comparative Development

2.2.2 Comparative Analysis of Human and Ape Development

2.2.3 Candidate Molecular Pathways Influencing Cortex Size

2.2.4 Comparative Genomics

2.2.5 Functional Studies of Candidate Genetic Changes

2.2.6 Systematically Analyzing Human-specific Mutations

2.3 Conclusion

References

3 Intermediate Progenitors in Neocortical Development and Evolution

3.1 Definition of Intermediate Progenitors

3.2 Historical Perspectives and the Discovery of IPs

3.3 Morphological Dynamics of IPs: From Apical to Basal

3.4 IP Subtypes and Transcriptomes

3.5 Epigenetic Regulation and IPs

3.6 Regulation of IP Genesis, Amplification, and Apoptosis

3.6.1 IP Genesis

3.6.2 IP Amplification

3.6.3 IP Apoptosis

3.7 Developmental Functions of IPs

3.7.1 Upper Layer Hypothesis

3.7.2 Radial Amplification of PNs

3.7.3 Gyrification

3.7.4 Delta-Notch Signaling

3.7.5 Epithelial-mesenchymal Transition and Planar Cell Polarity

3.7.6 IPs in Axon Development

3.7.7 Interneuron Guidance and Reciprocal Signaling

3.7.8 IPs in Rostro-caudal Patterning

3.8 IPs, Tbr2, and Cerebral Cortex Evolution

3.8.1 Mammals

3.8.1.1 Eutheria

3.8.1.2 Metatheria

3.8.1.3 Prototheria

3.8.2 Birds

3.8.3 Reptiles

3.8.4 Amphibians

3.8.5 Fish

3.8.6 Conclusions on the Evolution of IPs

3.9 IPs and Human Brain Malformations

3.10 Future Directions

References

4 Area V1 Development, a Model System to Link Corticogenesis to Adult Cortex Structure and Function

4.1 Introduction

4.2 The Outer Subventricular Zone: A Uniquely Specialized and Enlarged Progenitor Pool in the Visual Primate Cortex

4.3 Primate OSVZ Progenitors are Endowed with Extended Proliferative Abilities

4.4 The Key Role of G1 Phase Regulation in the Primate OSVZ Progenitors Expansion

4.5 G1 Phase Regulation Underpins Cortical Cytoarchitecture

4.6 Extrinsic Control of OSVZ Progenitors Cell-cycle by Thalamocortical Axons in Area V1

4.7 Complex Lineages in OSVZ Progenitors and Generation of SG Neuron Diversity

4.8 The Role of OSVZ beyond Proliferation: An Area-specific Scaffold for Radial Migration

4.9 Bringing into Line Understanding of the Development of Cortex with Modern Concepts of Cortical Function

Acknowledgments

References

5 Neocortical Neurogenesis in Amniote Evolution

5.1 Introduction

5.2 Cerebral Cortex Development in Mouse

5.2.1 Progenitors in Ventricular Zone: NECs and aRGCs

5.2.1.1 NECs

5.2.1.2 aRGCs

5.2.2 Progenitors in the Subventricular Zone: IPCs and bRGCs

5.2.2.1 IPCs

5.2.2.2 bRGCs

5.2.3 Neuronal Radial Migration

5.3 Sauropsids

5.3.1 Homologies and Organization of the Pallium

5.3.1.1 Conservation and Divergence of Progenitor Cell Types

5.3.1.2 Absence of a Bona Fide SVZ

5.3.1.3 Generation and Spatial Distribution of Neurons

5.4 Higher Mammals: Increase in Cortical Size and Complexity

5.4.1 Progenitor Cell Behavior and Regulation

5.4.1.1 NECs

5.4.1.2 aRGCs and the Generation of bRGCs

5.4.1.3 Outer Subventricular Zone Formation and Expansion

5.4.1.4 Radial Migration of Neurons and Tangential Expansion

References

6 Dynamic Transcriptional Control of Neural Stem Cells

6.1 Introduction

6.2 Regulation of NSC Proliferation and Differentiation by bHLH Transcription Factors

6.3 Dynamic Control of Notch Signaling in NSCs

6.4 Regulation of Boundary Cell or Astrocyte Formation by Sustained Hes1 Expression

6.5 Regulation of NSC Proliferation by Oscillatory Hes1 Expression

6.6 Conclusions

Acknowledgments

References

7 Mechanical and Physical Interactions Involving Neocortical Progenitor Cells

7.1 Introduction

7.2 Mechanical Forces Generated, Used, and Managed by Neocortical VZ Cells

7.2.1 The Ventricular Zone is Dynamically Composed of Bidirectionally Moving Nuclei/somata of NPCs

7.2.2 The Apical Surface is Actively Contractile

7.2.3 Normal Subapical Crowding Induces Elasticity-mediated Passive Nucleokinesis

7.2.4 Overcrowding, Likely Sensed Periapically by NPCs, Disrupts VZ Integrity

7.2.5 Curvature and Stiffness of the Apical Surface in Region Specificity and Evolution

7.3 Mechanical Influences of Differentiating Neurons on Progenitor Cells

7.3.1 The SVZ Mechanically Fences IKNM and the VZ and Safeguards Apical Cytogenesis

7.3.2 The Earliest-born Neurons’ Dorsal-to-ventral Streaming Deflects RFs, Setting up Ventrally Spread Corticogenesis

7.3.3 Compressively Packed Neurons Stretch Axons along the Dorso-ventral Axis

7.3.4 Compressively Packed Neurons also Apicobasally Stretch RFs

7.3.5 Apical Surface Contractility Underlies Wall Thickening via Circumferential Compression of Intramural Components and Inward Pulling

7.4 Mechanical Influences on NPCs from the Components that Sandwich the Cerebral Wall

7.5 Discussion and Perspectives

7.5.1 Sensing and Actuation

7.5.2 Prestress and Self-tightening

7.5.3 Measurement and Simulation

Acknowledgment

References

8 The Role of Human-specific Genes and Amino Acid Substitutions for Neocortex Expansion and Modern Human vs. Neanderthal Differences in Neocortical Neurogenesis

8.1 Introduction

8.2 Cortical Neural Stem and Progenitor Cells

8.2.1 Apical Progenitors

8.2.2 Basal Progenitors – Advantages for Neocortex Expansion

8.3 Human-specific Genes Preferentially Expressed in cNSPCs – ARHGAP11B

8.3.1 ARHGAP11B – Molecular Features and Expression in cNSPCs

8.3.2 ARHGAP11B – Basal Progenitor Amplification

8.3.3 ARHGAP11B – Neocortex Expansion

8.3.4 ARHGAP11B – Enhanced Cognitive Abilities

8.3.5 ARHGAP11B – Mechanism of Action

8.4 Human-specific Amino Acid Substitutions in cNSPC-active Proteins – Differences in Cortical Neurogenesis between Modern Humans and Neanderthals

8.4.1 Chromosome Segregation upon Apical Progenitor Mitosis

8.4.1.1 Mitotic Differences among Hominid Neural Stem and Progenitor Cells

8.4.1.2 Spindle Orientation of Apical Progenitors

8.4.1.3 Metaphase Prolongation of Apical Progenitors

8.4.1.4 Mitotic Differences between Modern and Archaic Human Apical Progenitors

8.4.1.5 Mechanism Underlying Metaphase Prolongation

8.4.1.6 Metaphase Prolongation and Increased Chromosome Segregation Accuracy

8.4.2 Neuron Production by Basal Radial Glia

8.4.2.1 NOVA1

8.4.2.2 Transketolase-like 1

8.5 Concluding Remarks

References

Part 2 Progenitor Lineages

9 Temporal Scaling: A Link between Conserved Neurogenic Processes and Differential Size in Mammalian Cortical Development

9.1 Conserved Fundamental Processes of the Cortical Development

9.2 The Formation of the Variety in Neural Stem Cells Promoting the Expansion of Brain Size in Evolution

9.2.1 Formation of New Germinal Zone during Corticogenesis

9.2.2 Evolutional Implication of the OSVZ and Gyrification

9.3 Variety of Progenitor Cells in the VZ

9.3.1 Truncated RGC is a Progenitor Subtype across Species

9.3.2 A Novel IPC Subtype Undergoing Interkinetic Nuclear Migration

9.3.3 Enormous Heterogeneity of Cell Lineages of RGC in the Presence sRGC

9.4 Temporal Scaling of Brain Development

9.4.1 Time Course of Cortical Development Scales

9.4.2 Mechanisms Underlying Scaling in Developmental Time

9.4.3 Evolution of Gene Regulatory Network and Species-specific Genes

9.4.4 Contribution of Epigenetic Control of Gene Regulatory Network

9.4.5 Impacts of Metabolism and Mitochondria

9.5 Conclusion

References

10 Interplay of Cell-autonomous Gene Function and Tissue-wide Mechanisms Regulating Radial Glial Progenitor Lineage Progression

10.1 Introduction

10.1.1 Cortical Development

10.1.2 Cell-autonomous Gene Function vs. Tissue-wide Regulation of RGP Lineage Progression

10.1.3 The MADM Principle

10.2 Cellular Features Orchestrating aRGP Lineage Progression

10.2.1 Cell Polarity in RGP Lineage Progression

10.2.1.1 Distinct and Sequential Roles of

Lgl1

along Cortical Development

10.2.2 Cell Division Regulation during Neocortical Development

10.2.2.1 The Cellular Landscape Influences

Sp2

Gene Function to Regulate Lower- or Upper-layer Neuron Formation

10.2.2.2

Lis1

Cell-autonomously Regulates aRGP Proliferation during Symmetrical Division State

10.2.2.3 The Cell-autonomous Neuron Survival Regulation by

Cdkn1c

is Masked by a Cellular Community Effect on Growth

10.2.3 Cell Survival Regulation during RGP Lineage Progression

10.2.3.1

Egfr

is Cell-autonomously Required for Astrocyte Production, but Orchestrates Neuronal Survival in a Non-cell-autonomous Manner through Glia-neuron Interactions

10.2.4 Transcriptional Regulation Guiding Faithful Cortical Development

10.2.4.1

Otx1

Regulates Neurogenesis Cell-autonomously in a Layer-independent Manner

10.2.4.2

Eed/PRC2

is not Cell-autonomously Required during Neurogenesis but at the Later Stage during Astrocyte Production

10.3 Concluding Remarks

Acknowledgments

References

Part 3 Generation of Neuron Types

11 Generation of Projection Neuron Diversity in the Neocortex: From Embryos to Organoids

11.1 Introduction

11.2 Basic Principles of Cellular Organization and Composition of the Cerebral Cortex

11.3 Diversity of Excitatory Projection Neurons

11.4 Developmental Origin of Projection Neurons: Progenitor Strategies

11.5 The Molecular Logic Underlying Projection Neuron Diversification: Postmitotic Mechanisms

11.6 The Emergence of Human Brain Organoids as Model Systems to Investigate Human-specific Features of Cortical Development

11.7 Cortical Cell Type Diversity and Cellular Specification in Human Brain Organoids: An Opportunity to Decipher How Human Neurons are Made

11.8 Concluding Remarks

Acknowledgments

Conflict of Interest Statement

References

12 Development of Cortical Neuron Heterogeneity and Impact of Neurodevelopmental Disorders

12.1 Identity of Precursors within the Neocortical Germinal Zones

12.2 Intermediate Precursor Cells

12.3 RNA Sequencing for Determination of Cell Type

12.4 Role of Neural Precursor Heterogeneity in Neocortical Development

12.4.1 Interlaminar Heterogeneity

12.4.2 Intralaminar Heterogeneity: Mapping the Output of Cortical Progenitor Cell Types

12.4.3 Precursor Effects on Gyrencephaly

12.5 Consequences of Altering Neurogenesis

12.5.1 Trisomy 21

12.5.2 Prenatal Viral Infection

12.6 Conclusion

References

13 Developmental and Evolutionary Origins of Cortical Projection Neuron Identity and Connectivity

13.1 Laminar Organization of the Cerebral Cortex

13.2 Developmental Origins of Cortical Projection Neurons

13.3 Molecular Mechanisms Governing the Laminar Identity of Cortical Projection Neurons

13.4 Molecular Mechanisms Governing the Areal Identity of Cortical Projection Neurons

13.5 Human Specializations of Cortical Projection Neurons and their Circuitry

13.6 Human Neurodevelopmental and Neuropsychiatric Disorders

13.7 Conclusions

Acknowledgments

References

14 Intrinsic and Input-dependent Development of Cortical Neuron Types

14.1 Developmental Emergence of Neocortical Areas

14.1.1 Input-independent Arealization

14.1.2 Input-dependent Arealization

14.1.2.1 Thalamic Input-dependent Emergence of Cortical Areas

14.1.2.2 Spontaneous Activity

14.1.2.3 Sensory Activity Sculpts Cortical Differentiation

14.1.2.4 Critical Periods of Plasticity

14.2 Cell-type Specific Input-dependent Differentiation

14.2.1 Generic Effects of Input/Activity on Neuronal Differentiation

14.2.2 L4 Neurons

14.2.3 L2/3 Neurons

14.2.4 Deep-layer Neurons

14.2.5 Cajal–Retzius and Subplate Neurons

14.2.6 Inhibitory Interneurons

14.2.7 Non-neuronal Cells

14.3 Outstanding Questions and Perspectives

References

15 Corpus Callosum Evolution and Development

15.1 Evolution of Telencephalic Commissures

15.1.1 Interhemispheric Connections in Vertebrates

15.1.2 Evolutionary Appearance of the CC

15.2 Molecular Characterization of Callosal Projection Neurons

15.2.1 SATB2, a Marker of CPNs

15.2.2 Gene Regulatory Networks in the Differentiation of Projection Neurons

15.2.2.1 Specification of Subcortical Projection Neurons

15.2.2.2 Generation of SATB2+CTIP2- Neurons

15.2.2.3 Generation of SATB2+CTIP2+ Neurons

15.2.2.4 BRN1/2 as Upstream Regulators of SATB2

15.2.2.5 Developmental Regulation of SATB2 Functions

15.2.3

Satb2

Expression in Acallosal Species

15.2.3.1 Evolving Functions of SATB2 and CTIP2

15.2.3.2 Heterochronicity of Neurogenesis and Onset of Satb2 Expression

15.2.4 Temporal and Spatial Regulation of Gene Expression in CPNs

15.2.4.1 Temporal Regulation of CPN Identity

15.2.4.2 Spatial Regulation of CPN Identity

15.2.4.3 Spatial Segregation of Callosal Axons

15.2.5 Evolutionary Regulation of Gene Expression in CPNs

15.2.5.1 Evolution of CPN Populations

15.3 Patterning of the Commissural Plate

15.4 Axon Guidance Mechanisms of CC Development

15.4.1 Molecular Machinery and Developmental Timing of Axonogenesis

15.4.1.1 Axon Growth Cone of CPNs

15.4.1.2 Timing of CPN Axonal Projection

15.4.2 Initiation of Axon Projection

15.4.2.1 Initiation of Pioneering Axons from the Cingulate Cortex

15.4.2.2 Differential Response to Chemotactic Cues in Early-born PNs

15.4.2.3 Medial Turn of Upper-layer CPNs

15.4.3 Guidance in the Subplate Compartment

15.4.4 Guidepost Populations at the Brain Midline

15.4.4.1 Midline Glia

15.4.4.2 Midline Neurons

15.5 Connection to the Contralateral Hemisphere

15.5.1 Determination of Connection Partners

15.5.1.1 Topographic Organization of Callosal Axons

15.5.1.2 Electrophysiological properties of CPNs

15.5.2 Developmental Exuberance and Pruning of Connections

15.5.2.1 Selective Pruning of Layer IV Contralateral Axons

15.6 The Adult Corpus Callosum

15.6.1 Histological and Functional Properties of Callosal Fibers

15.6.1.1 Connection of Motor and Sensory Cortices

15.6.1.2 Evolution of Brain Lateralization

15.6.2 Excitatory and Inhibitory Roles of the CC

15.7 CC Agenesis and Developmental Plasticity in the Human Brain

15.7.1 Etiology of CC Agenesis

15.7.2 CC Agenesis in Autism Spectrum Disorder and Intellectual Disability

15.7.3 Developmental Plasticity in CC Agenesis

15.8 Conclusion

Acknowledgments

References

16 Towards the Transcriptionally based Classification of L6b in the Adult Mouse Brain

16.1 Introduction

16.2 Traditional Literature Data

16.2.1 Traditional Markers Identified by Layer-specific Gene Expression Analysis:

16.2.2 Morphology and Electrophysiology

16.2.3 Connectivity

16.3 The Problem of Biological Classification

16.4 Analysis of Classical Markers in Global Transcriptomic

16.5 The Use of Transcriptomics as a Classing Factor

16.6 Orexin Receptor Expressing L6b Superclass

16.7 Conclusions

Acknowledgments

References

Part 4 Neuron Migration

17 Cortical Neuron Migration in Health and Disease

17.1 Modes of Cell Migration in the Forebrain: From Rodents to Primates

17.1.1 Projection Neurons

17.1.2 Interneurons

17.2 Prototypic Neuronal Migration Disorders

17.2.1 Lissencephaly

17.2.2 Cobblestone Dysplasia

17.2.3 Periventricular Nodular Heterotopia

17.2.4 Subcortical Band Heterotopia

17.3 Molecular Mechanisms Regulating Neuronal Migration

17.3.1 Transcriptional Programs

17.3.1.1 Proneural bHLH Genes

17.3.1.2 Homeobox Transcription Factors

17.3.2 Unconventional Cytoskeletal Modulators

17.3.3 Environmental Factors

17.3.3.1 Secreted Factors

17.3.3.2 Extracellular Matrix

17.3.3.3 Extracellular Vesicles

17.4 Crosstalk between Migrating Cells to Control Cortex Morphogenesis

Acknowledgments

References

18 The Emerging Roles of LIS1 Biomechanics in Cellular and Cortical Homeostasis

18.1 LIS1 and Brain Structure, an Introduction

18.2 LIS1, the Protein

18.3 Known LIS1 Functions

18.4 LIS1 is an RNA Binding Protein

18.4.1 RNA Transcription and Splicing

18.4.2 RNA Polyadenylation and Export

18.4.3 Protein Translation

18.4.4 mRNA Stability and Degradation

18.5 LIS1 and Mechanotransduction

18.6 Modeling Cortical Folds and Lissencephaly in Human Brain Organoid Models

Acknowledgments

References

Part 5 Neural Patterning, Specification of Cortical Regions

19 Understanding Human Forebrain Morphogenesis and Early Expansion Using Organoids

19.1 Introduction

19.2 A Brief History of Neural Organoids

19.3 Early Forebrain Morphogenesis

19.3.1 Neural Specification and Patterning

19.3.2 Neural Tube Formation

19.3.3 Forebrain Expansion

19.4 Organoid Models

19.4.1 Neural Patterning In Vitro

19.4.2 Neural Tube Modelling

19.4.3 Modelling Early Forebrain Expansion

19.4.4 Modelling Human Disorders of Forebrain Expansion

19.4.5 Evolutionary Insight

19.5 Conclusion

Acknowledgments

References

20 Early Neuronal Differentiation/patterning of the Human Pallium, Modeling by in Vitro Systems, and Disruption in Developmental Disorders

20.1 Regulation of Axial Development

20.1.1 Formation of Brain Regions after Neurulation

20.1.2 Organizers: Signaling Centers Involved in Patterning

20.1.2.1 WNT, Fibroblast Growth Factors, and Bone Morphogenetic Protein

20.1.2.2 Sonic Hedgehog

20.1.2.3 Retinoic Acid

20.1.3 Translation into In Vitro Systems: Monolayers and Organoid Models

20.2 Patterning of the Cortical Plate and Cell Diversity

20.2.1 Preplate and Early Neurogenesis

20.2.2 Dorsal Cortex Neurogenesis

20.2.2.1 Diversity of Human Radial Glial Cells

20.2.2.2 Fate Mapping and the Control of Cortical Cell Diversity

20.2.2.3 Regional Specification

20.2.3 Origin of Inhibitory Neurons in Humans

20.3 Modeling Disorders of Cortical Development In Vitro

20.3.1 Altered Brain Growth

20.3.2 Excitatory/inhibitory Lineage Imbalance

20.3.3 Human-specific Features

References

21 Mammalian Cortical Regional Specification

21.1 Introduction: Embryonic Anatomy that Contributes to Early Cortical Development

21.1.1 Prosencephalon

21.1.2 Pallial Progenitors

21.1.3 Subpallium

21.2 Pallial Patterning

21.2.1 Transcription Factors

21.2.2 Patterning of the Developing Cortex by TFs

21.2.2.1 A Screen to Discover New Patterning TFs

21.2.2.2 TFs that Regulate Cortical Patterning

21.2.2.3 General Precepts of TF Regulation of Cortical Patterning

21.2.2.4 Maintaining the Pallial–subpallial Boundary: An Important Role for Cortical Patterning TFs

21.2.2.5 Uncovering Roles for Other TFs with Gradients of Expression in the VZ – Cortical Regionalization TF Network

21.2.2.6 TFs Involved in the Arealization of the SVZ and CP – How the Pallial Protomap is Propagated into the Maturing Cortex

21.3 Transcriptional Circuits in Pallial Patterning

21.3.1 Enhancers May Regulate the Formation of the Cortical Protomap

21.3.1.1 Defining and Identifying an Enhancer

21.3.1.2 Identifying Enhancers Involved in Cortical Patterning and Deciphering a TF Code for Cortical Regional/areal Specification

21.3.1.3 Epigenetic Regulation of Enhancer Regions and Genes – Transcriptional Regulators

21.3.1.4 Conservation and Function of Pallial Enhancers

21.4 Conclusion

References

22 Development of the Neocortical Area Map

22.1 Introduction

22.1.1 Classic Models of Neocortical Area Patterning

22.2 Thalamic Mechanisms of Area Development

22.2.1 Thalamic Axon Trajectories and Establishing Area Position

22.2.2 Active Thalamic Innervation Determines Function in a Cortical Area

22.2.3 Plasticity of Sensory Area Size

22.2.4 Thalamic Activity and Somatosensory Barrel Fields

22.2.5 Transcription Factor

Lhx2

Allows S1 Cortex to Respond to Thalamic Input

22.3 Mechanisms of Area Patterning Intrinsic to Neocortex

22.3.1 Neocortex is Not a Blank Slate at Birth

22.3.2 Secreted Signaling Molecules that Establish Area Position

22.3.3 Fibroblast Growth Factor FGF8 Controls anterior to posterior (A/P) Area Position in the Map

22.3.4 FGF8 Indirectly Controls Trajectories of Thalamic Axons

22.3.5 Thalamic Axon Guidance Cues in the Subplate and Neocortex

22.3.6 Neocortical Patterning by the Cortical Hem

22.3.7 Emx2, Dmrt3 and 5, Nr2f1, and Cortical Patterning

22.3.8 Graded Expression of Transcription Factors

22.3.9 Mapping the Neocortical Primordium with Forebrain Enhancers

22.4 Conservation of Patterning Mechanisms among Different Mammalian Species

22.4.1 Mouse, Ferret, and Human

22.5 Conclusions

References

Part 6 Cortical Folding

23 Old Models Know Wrinkles Best: A Critical Review on the Mechanisms of Cortical Gyrification

23.1 The Early Studies on Gyrification

23.2 Quantification of Gyrification: The Gyrification Index

23.3 The Reason for Gyrification

23.4 Gyrification Features

23.5 Gyrification and Brain Size

23.6 Patterns of Cortical Gyrification

23.6.1 Correlation between Gyral Morphology and Cortical Function

23.7 Mechanisms Underlying Gyrification

23.7.1 Gyrification as a Consequence of Space Constrains

23.8 Cortical Expansion and Differential Growth of Cortical Layers

23.9 Gyrogenesis Hypothesis

23.10 Axon Tension Hypothesis

23.10.1 Differential Neurogenic Hypothesis

23.11 Our Proposal: Gyrification is Produced by Explosive Cortical Expansion Dominated by Axonal and Glial Invasion and Cortical Differentiation

23.12 The Subplate and Axonal Afferents, Cortical Maturation, and Gyrification

23.13 Loss of Axonal Input and Gyrification

23.14 Conclusion

Acknowledgments

References

24 Investigation of the Mechanisms Underlying the Development and Evolution of the Cerebral Cortex Using Gyrencephalic Ferrets

24.1 Introduction

24.2 Developmental Processes of the Cerebral Cortex

24.3 Structural and Developmental Features of Cortical Folds

24.4 Hypotheses on the Mechanisms of Cortical Folding

24.5 Investigations of the Mechanisms of Cortical Folding using Mice

24.6 Ferrets as a Model Animal for Investigating the Development and Evolution of the Cerebral Cortex

24.7 Development of Genetic Manipulation Techniques for the Ferret Brain

24.8 Investigation of the Mechanisms Underlying the Development and Evolution of the Cerebral Cortex using Ferrets

24.8.1 The Roles of Neural Progenitors in Cortical Folding

24.8.2 Mechanisms Regulating the Abundance of Neural Progenitors

24.8.3 Investigation of the Mechanisms Underlying Cortical Folding using Ferrets

24.8.4 Common and Species-specific Mechanisms of Cortical Folding

24.9 Developmental Processes and Evolution of Fiber Layers in the Cerebral Cortex

24.10 Future Prospects

Acknowledgments

References

Part 7 Cortical Development: Variations, Disorders, and Malformations

25 Genetic Variation Altering Cortical Progenitor Function Leads to Human Brain Evolution and Interindividual Differences in Human Brain Structure

25.1 Introduction

25.2 Cellular Processes Occurring during Human Corticogenesis

25.3 Genetic Variation Shaping the Human Cortex

25.4 Model Systems for Studying Rare Variation

25.5 Rare Genetic Variation Impacting Cortical Progenitor Function

25.6 Model Systems for Studying Common Genetic Variants

25.7 Common Genetic Variants Influencing Cortical Size

25.8 Uncovering Evolutionarily Relevant Genetic Variants Influencing Human Cortical Structure

25.9 Discussion and Future Perspectives

References

26 Human Neocortical Evolution and Neurological Disorders

26.1 Introduction

26.2

SRGAP2C

26.2.1 Overview

26.2.2 Functional Analysis

26.2.3 Evolution

26.2.4 Other Segmental Duplications

26.3

ASPM

26.3.1 Overview

26.3.2 Primary Microcephaly

26.3.3 Functional Analysis

26.3.4 Evolution

26.4

GPR56

26.4.1 Overview

26.4.2 Bilateral Frontoparietal Polymicrogyria

26.4.3 Functional Analysis

26.4.4 Evolution

26.5 Human Accelerated Regions

26.5.1 Overview

26.5.2 Definition and Discovery

26.5.3 Genes and Neurological Disorders Associated with Human Accelerated Regions

26.6 Conclusions

Acknowledgments

References

27 Clinical and Molecular Overview of Cortical Malformations

27.1 Concept of Cortical Malformations and Clinical Features

27.2 Progenitors: Proliferation and Apoptosis

27.2.1 Microcephaly

27.2.2 mTORopathies and Megalencephaly

27.3 Neurons and Neuronal Migration

27.3.1 Lissencephaly

27.3.2 Heterotopias

27.3.2.1 Periventricular Heterotopia

27.3.2.2 Subcortical Band Heterotopia

27.3.3 Polymicrogyria

27.4 Interneurons and Focal Cortical Dysplasia

27.4.1 Glial Cells (Microglia, Astrocytes, and Oligodendrocytes)

27.5 Other Levels of Complexity Contributing to Cortical Malformations

27.5.1 Cortical Connectivity

27.5.2 Extrinsic Factors (Cell Adhesion, ECM, Secreted Molecules)

27.5.3 Environment

27.5.3.1 Ethanol

27.5.3.2 Inflammation

27.5.3.3 Viruses

27.5.3.4 Radiation

27.5.4 Clinical Heterogeneity

27.6 Human and Animal Models

References

Part 8 Overarching Topics

28 Posttranscriptional Control of Brain Development

28.1 Introduction

28.1.1 Cortical Development Overview

28.1.2 Cis and Trans Control of RNA

28.2 Splicing

28.2.1 Alternative Splicing in the Brain

28.3 Stability and Exon Junction Complex

28.3.1 The Exon Junction Complex

28.3.2 RNA Decay Mechanisms

28.4 Translational Control

28.4.1 Translational Regulators

28.4.2 mRNA Transport, Localization, and Local Translation

28.5 Noncoding RNAS: miRNAs, lncRNAs, and circRNAs

28.6 RNA Editing and Modifications

28.7 Conclusions and Future Directions

References

29 Regulation of mRNA Localization and Translation in Brain Development: Implications for the Mechanism Leading to the Brain Evolution and Pathogenesis

29.1 Introduction

29.2 The Roles of FMRP Target mRNAs as Responsible Factors of Fragile X Syndrome

29.2.1 FMRP Functions in the Brain

29.2.2 FMRP Target mRNAs in the Central Nervous System

29.2.3 FMRP Targets with Regard to Brain Development and Diseases

29.3 mRNA Transport of a Cell Cycle Regulator Ccnd2

29.3.1 Functions of Cyclin D Family Members in RG Cells

29.3.2 Ccnd2 mRNA Transport from the Cell Soma to the Basal Endfoot in RG Cells

29.3.3 Possible Regulation of Ccnd2 mRNA Transport in RG Cells

29.3.4 Hypotheses of the Role of Ccnd2 Transport System during Brain Evolution

29.3.5 Ccnd2 Functions Related to Human Diseases

29.4 Conclusion

Author contributions

Funding

References

30 Signal Transduction during Cortical Neurogenesis

30.1 Introduction

30.2 Wnt/β-catenin Signaling

30.2.1 Wnt/β-catenin Signaling is Essential for Neurogenesis

30.2.2 CTNNB1 (β-catenin Encoding Gene) and Microcephaly

30.2.3 Wnt/β-catenin Signaling in Autism Spectrum Disorders

30.3 Notch Signaling

30.3.1 The Core Components of Notch Signaling

30.3.2 Dynamic Regulation of Notch Signaling Modulates Neurogenesis

30.3.3 Notch Signaling and Neuronal Migration

30.4 BMP2-SMAD Signaling

30.5 Sonic Hedgehog Signaling Pathway

30.5.1 SHH Signaling Coordinates the Proliferation and Differentiation of Neural and Glial Progenitor Cells

30.5.2 Mutations in SHH-Associated Genes Cause Holoprosencephaly

30.6 Other Signaling Pathways: c-Jun N-terminal Kinase, Fibroblast Growth Factors, and Retinoic Acid Signaling

30.7 The Crosstalk between Different Signaling Pathways during Neurogenesis

30.8 Concluding Remarks

Acknowledgments

References

31 Centrosome Regulation and Function in the Developing Neocortex

31.1 Centrosome Structure, Biogenesis, and Function

31.1.1 The Continuous Understanding of the Centrosome

31.1.2 The Centrosome Duplication Cycle

31.1.3 Centrosome Function in Animal Cells

31.2 Neocortical Development

31.2.1 Organized Progenitor Cell Behavior and Neocortical Histogenesis

31.2.2 Neuronal Migration and Differentiation

31.3 Centrosome Regulation and Function in RGPs

31.3.1 Intricate Centrosome Organization in RGPs

31.3.2 Neocortical Neurogenesis in the Absence of the Centrosome

31.3.3 Asymmetric Centrosome Inheritance in Dividing RGPs

31.3.4 Mitotic Spindle Orientation and Daughter Cell Fate Specification

31.3.5 Primary Cilium Regulation and Function in RGPs

31.3.6 Other Emerging Roles of the Centrosome in RGPs

31.4 Centrosome Regulation and Function in Neuronal Migration

31.4.1 The Centrosome and Two-stroke Neuronal Locomotion

31.4.2 Centrosome Positioning in Migrating Neurons

31.4.3 The Centrosome and Tangential Neuronal Migration

31.5 Centrosome Regulation and Function in Neuronal Polarization

31.5.1 Centrosome Positioning and Axon Specification in Cultured Neurons

31.5.2 The Centrosome and Neuronal Polarization In Vivo

31.5.3 Interplay of Microtubule and Actin Regulation during Neuronal Polarization

31.6 The Centrosome and Neocortical Developmental Diseases

31.6.1 Centrosomal Defects and Microcephaly

31.6.2 Centrosomal Defects and Neuronal Migration Disorders

31.6.3 Centrosomal Defects and Ciliopathies

31.6.4 Centrosomal Defects and Megalencephaly

31.7 Concluding Remarks

Acknowledgments

References

32 Keeping the Cortex Afloat: Cerebrospinal Fluid Contributions to Cerebral Cortical Development

32.1 Introduction: Development of CSF-filled Ventricles

32.2 The Brain Fluid Environment during Forebrain Development

32.2.1 Generating a Brain Fluid Environment during Neurulation and Forebrain Progenitor Expansion

32.2.2 Production of CSF during Cerebral Cortical Development

32.2.2.1 Choroid Plexus

32.2.2.2 Ependymal Cells

32.2.3 Functions of CSF Contents during Early Cerebral Cortical Development

32.2.3.1 Composition of the Developing CSF

32.2.3.2 Proteins and Peptides

32.2.3.3 Small Molecules and Ions

32.2.4 CSF Movement: Fluid Production, Dynamics, and Outflow

32.2.4.1 Fluid Production

32.2.4.2 CSF Movement and Fluid Dynamics

32.2.4.3 Motile Cilia Generated Flow

32.2.4.4 CSF Outflow Routes

32.2.5 Barrier Properties

32.3 Tools and Therapeutics

32.3.1 Approaches to Modulate CSF Composition

32.3.2 Therapeutic Potential for Neurodevelopmental Disorders

32.4 Summary and Future Directions for the Field

32.4.1 Summary

32.4.2 Future Directions

32.4.2.1 Modulating CSF Composition?

32.4.2.2 CSF Fluid Clearance from Developing Ventricles?

32.4.2.3 Clearance of Toxic Factors from Developing CSF?

Acknowledgments

References

33 Comparative Cognitive Neuroscience and Dorsal and Ventral Streams in Primates

33.1 Introduction

33.2 Brain Size and Relative Brain Size

33.3 Neuron Numbers in Neocortex

33.4 Increasing the Complexity of Cortical Processing: The Dorsal Stream

33.5 The Ventral Stream of Visual Processing

33.6 Cognition in Apes and Humans

33.7 Language, Speech, and Reading

33.8 Primate Memory and Prefrontal Cortex

33.9 Conclusions

References

Index

End User License Agreement

List of Tables

CHAPTER 03

Table 3.1 Tbr2 and progenitor...

CHAPTER 15

Table 15.1 Cortical location of...

CHAPTER 16

Table 16.1 Available data on...

CHAPTER 18

Table 18.1 LIS1-RNP complexes...

CHAPTER 21

Table 22.1 The TF that...

CHAPTER 30

Table 30.1 Effects of Notch...

CHAPTER 31

Table 31.1 Centrosome-related genes...

CHAPTER 32

Table 32.1 Developmental ion concentrations...

List of Illustrations

CHAPTER 01

Figure 1.1 Radial glia cell...

Figure 1.2 Basal radial glia...

Figure 1.3 Radial glia throughout...

CHAPTER 02

Figure 2.1 Progenitor diversity and...

CHAPTER 03

Figure 3.1 IPs are generated...

Figure 3.2 IP-selective molecular...

Figure 3.3 Developmental functions of...

CHAPTER 04

Figure 4.1 Summary of conspicuous...

Figure 4.2 Dynamics of cortical...

CHAPTER 05

Figure 5.1 Cell distribution in...

Figure 5.2 Stem cells in...

Figure 5.3 Different types of...

Figure 5.4 Cell mechanism of...

CHAPTER 06

Figure 6.1 Expression dynamics of...

Figure 6.2 Optogenetic control of...

Figure 6.3 Oscillatory expression in...

Figure 6.4 Notch signaling in...

Figure 6.5 Mathematical modeling of...

Figure 6.6 The phenotypes of...

CHAPTER 07

Figure 7.1 Clonal and in...

Figure 7.2 Contractility of the...

Figure 7.3 Dorsal-to-ventral...

Figure 7.4 Passive stretching of...

Figure 7.5 Mechanical relationship between...

CHAPTER 08

Figure 8.1 Effects of human...

CHAPTER 09

Figure 9.1 Mammalian cortical development...

Figure 9.2 An example of...

Figure 9.3 Comparison of temporal...

CHAPTER 10

Figure 10.1 The quantitative framework...

Figure 10.2 Comparative extrinsic and...

Figure 10.3 The MADM experimental...

Figure 10.4 Cell-autonomous gene...

CHAPTER 11

Figure 11.1 Distribution of excitatory...

Figure 11.2 The developing mammalian...

Figure 11.3 Human brain organoids...

CHAPTER 12

Figure 12.1 UMAPs based on...

Figure 12.2 Tbr2 (EOMES) fate...

CHAPTER 13

Figure 13.1 Major neuronal subtypes...

Figure 13.2 Schematic of projection...

Figure 13.3 Language-related pathways...

Figure 13.4 Timeline of key...

CHAPTER 14

Figure 14.1 Cell-intrinsic and...

Figure 14.2 Expansion of cortical...

Figure 14.3 Organization of the...

Figure 14.4 Sensory information reaches...

Figure 14.5 Emergence of first...

Figure 14.6 Thalamic activity shapes...

Figure 14.7 Input deprivation prevents...

Figure 14.8 Relationships between cortical...

Figure 14.9 Layer 4 spiny...

Figure 14.10 Balanced activity is...

CHAPTER 15

Figure 15.1 Evolution of telencephalic...

Figure 15.2 Mouse models of...

Figure 15.3 Stages of callosal...

Figure 15.4 Axon guidance mechanisms...

Figure 15.5 The adult human...

CHAPTER 16

Figure 16.1 Overview of computational...

Figure 16.2 (A) Transcriptomic 2D...

Figure 16.3 Graphical reproduction of...

Figure 16.4 Overview of input...

Figure 16.5 Expression of (A...

Figure 16.6 Representation of L6b...

Figure 16.7 Traditional markers in...

CHAPTER 17

Figure 17.1 Neurogenesis and migration...

CHAPTER 18

Figure 18.1 Schematic presentation of...

Figure 18.2 The LIS1 interactome...

Figure 18.3 LIS1 dosage influences...

Figure 18.4 (A) Cell lineages...

CHAPTER 19

Figure 19.1 Patterning of the...

Figure 19.2 Mechanisms influencing brain...

Figure 19.3 Organoid models of...

CHAPTER 20

Figure 20.1 Neurulation process and...

Figure 20.2 The developing human...

CHAPTER 21

Figure 21.1 (A) Schematics of...

Figure 21.2 (A) Representation of...

Figure 21.3 (A) Schematic indicating...

Figure 21.4 (A) Schematic of...

CHAPTER 22

Figure 22.1 Areas are outlined...

Figure 22.2 Duplicate S1 barrel...

Figure 22.3 Brains with the...

CHAPTER 23

Figure 23.1 Phylogenetic similitudes and...

Figure 23.3 Variability in the...

Figure 23.2 Variation in gyrification...

Figure 23.4 Correlation between gyrification...

Figure 23.5 Physical and numerical...

Figure 23.6 Subplate and gyrogenesis...

Figure 23.7 Cortical plate surface...

Figure 23.8 Changes in gyral...

CHAPTER 24

Figure 24.1 A ferret and...

Figure 24.2 Neural progenitors in...

Figure 24.3 In vivo genetic...

Figure 24.4 A working model...

Figure 24.5 A working model...

CHAPTER 25

Figure 25.1 Radial unit hypothesis...

Figure 25.2 Proposed cellular mechanisms...

Figure 25.3 Brain structure population...

Figure 25.4 Developing cortical wall...

Figure 25.5 Genome annotation showing...

Figure 25.6 Example annotated plot...

CHAPTER 27

Figure 27.1 Schematic overview of...

Figure 27.2 Summary of lissencephaly...

Figure 27.3 Summary of polymicrogyria...

CHAPTER 28

Figure 28.1 Posttranscriptional regulation of...

Figure 28.2 Dysregulation of posttranscriptional...

CHAPTER 29

Figure 29.1 mRNA regulation by...

Figure 29.2 Working model of...

CHAPTER 30

Figure 30.1 Schematic illustration of...

Figure 30.2 Mutations of β...

Figure 30.3 Dynamic regulation of...

Figure 30.4 Roles of bone...

Figure 30.5 Sonic hedgehog (SHH...

CHAPTER 31

Figure 31.1 Centrosome biogenesis and...

Figure 31.2 Centrosome function and...

Figure 31.3 Centrosomes, primary cilia...

Figure 31.4 Neuronal polarization and...

CHAPTER 32

Figure 32.1 Development of the...

Figure 32.2 Embryonic and postnatal...

Figure 32.3 Development of the...

Figure 32.4 Embryonic mouse CSF...

Figure 32.5 Mitochondrial changes during...

Figure 32.6 Embryonic CSF composition...

Figure 32.7 Ventricle-contacting cilia...

Figure 32.8 Ex vivo experimental...

Figure 32.9 In vitro experimental...

Figure 32.10 In vivo experimental...

CHAPTER 33

Figure 33.1 Patterns of feedforward...

Guide

Cover

Title Page

Copyright Page

Dedication

Table of Contents

Foreword

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Foreword

Understanding the human brain is a fundamental challenge. Key to this challenge is gaining insight into the development of the brain and how it changed during human evolution. This book Neocortical Neurogenesis in Development and Evolution, edited by Wieland B. Huttner, a pioneer in the cell biology of brain development, focuses on neurons, the crucial cell type of the brain, and the neocortex, the seat of higher-order brain functions. Its 33 chapters, contributed by leading researchers, provide a state-of-the-art overview of how the various types of cortical neurons are generated from cortical stem and progenitor cells. They also cover related topics such as the folding of the neocortex to accommodate larger numbers of neurons in the skull, and disorders of cortical development and their clinical implications. The book provides a unique blend of insight into neocortex development and its evolution that will be useful for both students and researchers in this fascinating field.

Svante Pääbo

2022 Nobel Prize in Physiology or Medicine

Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany

Preface

The evolution of mammalian brains, notably that of the human brain, has fascinated researchers for a long time. Inseparably linked to this evolution is the process of the development of mammalian brains. In this context, a mammalian-specific part of the brain that is of particular interest is the neocortex, the phylogenetically youngest part of the cerebral cortex. The neocortex is the seat of: sensory perception, generation of motor commands, and higher-order brain functions such as cognition and – in humans – language. An essential foundation underlying neocortex function is neurogenesis, a complex process in which the generation of neurons from cortical stem and progenitor cells (cSPCs) has a central role, but which also comprises subsequent steps such as the migration of new-born neurons to the appropriate neuronal layer of the six-layered neocortex. Topics inherent in or related to neocortical neurogenesis include (i) cell lineages within the various cSPCs and from cSPCs to neurons, (ii) the generation of diverse types of neurons, (iii) the specification of cortical regions, (iv) cortical folding, and (v) cortical malformations. It is precisely these issues that this book addresses.

I am grateful, and indeed feel honored, that of the leading researchers – and in fact pioneers – in the field whom I approached, the overwhelming majority agreed to become contributors to this book. Thanks to the wonderful efforts and major discoveries of these many colleagues and their associates, the 33 chapters of this book together provide a near-comprehensive up-to-date overview of neurogenesis in the developing neocortex and its evolutionary adaptations.

Before describing the various sections and chapters of this book, a brief introduction to the germinal zones, classes and types of cSPCs, and their terminology may be helpful. The wall of the developing neocortex with its various zones and layers arises from the neuroepithelium and retains a fundamental feature of the latter – apical–basal polarity. Thus, the ventricular surface corresponds to the apical side of the developing cortical wall, and the pial surface to its basal side. There are two principal germinal zones. First, the ventricular zone (VZ); it is the primary germinal zone, is the apical-most zone of the developing cortical wall, borders the ventricle, and is the zone most closely related to the neuroepithelium. Second, the subventricular zone (SVZ); it is a secondary germinal zone arising from the VZ and is located adjacent to the basal side of the VZ. In many mammalian species, notably those developing a relatively large and folded (gyrencephalic) neocortex such as the human, the SVZ is divided into two subzones, called the inner SVZ (iSVZ), which is located basally to the VZ, and the outer SVZ (oSVZ), which is located basally to the iSVZ. In line with this localization of the germinal zones along the apical–basal axis of the developing cortical wall, the cSPCs whose cell bodies reside in the VZ constitute one cSPC class and are collectively referred to as apical progenitors (APs), and the cSPCs whose cell bodies reside in the SVZ constitute the other cSPC class and are collectively referred to as basal progenitors (BPs). The major types of APs are the neuroepithelial cells, which transform into radial glia and are called either apical or ventricular radial glia; in turn these transform into the truncated radial glia. Additional types of APs are discussed in the respective chapters. The major types of BPs are the basal intermediate progenitors, sometimes simply referred to as intermediate progenitors, and the delaminated radial glia called either basal or outer radial glia.

The first section of the book focuses on cSPCs and the germinal zones in which they reside. Magdalena Götz and Florencia Merino open this section with their chapter describing the discovery and role of radial glial cells as neural stem cells. Arnold Kriegstein and Alex Pollen then review the diversity of cSPCs in the developing human neocortex and discuss how the contribution of progenitor cells to the structure of the neocortex underwent changes in the course of human evolution. This is followed by Robert Hevner’s chapter, which focuses on the role of one type of BP, the intermediate progenitors, in the development and evolution of the neocortex. Colette Dehay and Henry Kennedy then concentrate on a germinal zone first described in the developing macaque neocortex, the oSVZ, whose BPs have a key role in shaping the cytoarchitecture, in particular, of the primate neocortex. Víctor Borrell and Virginia Fernández subsequently broaden the evolutionary aspects of the role of cSPCs in neocortex development by comparing the cSPC-based neurogenesis in mammalian brains to the neurogenesis and progenitor cells in the developing brains of reptiles and birds. The following two chapters address two specific features of cSPCs. Ryoichiro Kageyama and Hiromi Shimojo concentrate on the role of basic helix-loop-helix transcription factors in the regulation of the proliferation and differentiation of neuroepithelial cells and radial glial cells. Takaki Miyata discusses biophysical issues, notably the mechanical forces that are relevant for the APs in the VZ, in particular the forces associated with the interkinetic nuclear migration of these cSPCs. Finally, my colleagues Lei Xing, Anneline Pinson, Felipe Mora-Bermúdez, and I discuss the role of human-specific genes and amino-acid substitutions that affect cSPC behavior and thereby influence human neocortex development in crucial ways, with relevance for neocortex expansion and modern human vs. Neanderthal differences in neocortical neurogenesis.

Linked to this discussion of the various classes and types of cSPCs and their key features, the following section of the book addresses, in two chapters, the topic of cell lineages within the various cSPCs and from cSPCs to neurons in the developing neocortex. Fumio Matsuzaki, Quan Wu, Merve Bilgic, and Yuji Tsunekawa first discuss the diversity of APs in the VZ and then report on the heterogeneity of radial glial cell lineages in the developing neocortex of the ferret, a gyrencephalic carnivore. This leads these authors to raise the issue of the temporal scaling of neocortex development, in the context of cSPC diversity, across three frequently studied mammalian species, the lissencephalic mouse, the gyrencephalic ferret and the highly gyrencephalic human. The second chapter in this section by Simon Hippenmeyer, Ana Villalba, and Nicole Amberg concentrates on the topic of radial glial cell lineage progression in the developing neocortex all the way to neurons and, eventually, to glial cells, and discusses cell-autonomous vs. non-cell-autonomous cues that affect this progression. In this context, the authors describe the MADM technology for the study of radial glial cell lineage progression and address specific genes that control this progression.

Following these two sections on cSPCs, the next section of the book addresses the generation of the various types of cortical neurons. Paola Arlotta and Ana Uzquiano open this section by discussing the mechanisms underlying projection neuron diversification and the use of human brain organoids to investigate human-specific features of neuron diversification. Tarik Haydar, Zhen Li, and William Tyler then link the topic of projection neuron diversity to the heterogeneity of cSPCs and discuss human developmental disorders resulting in alterations of cortical neurogenesis that affect neuron diversity. Nenad Sestan and his associates Navjot Kaur, Rothem Kovner, and Kevin T. Gobeske further broaden these discussions not only by addressing the topics of laminar and areal identity of cortical projection neurons, but also by introducing the subjects of human specializations of cortical projection neurons and their circuitry, and of human neuropsychiatric disorders. Denis Jabaudon, Esther Klingler, and Sergi Roig Puiggros then focus on cell-intrinsic and cell-extrinsic mechanisms that are involved in the emergence of cortical areas, and address the topic of input-dependent differentiation of the various types of cortical neurons, including the inhibitory interneurons. A different facet is introduced in the chapter by Jürgen Knoblich and Catarina Martins-Costa, who dissect the evolution and development of the corpus callosum, a key structure for the transfer of information between the brain hemispheres. Finally, Zoltán Molnár, Thomas Henning, and Sara Bandiera close this section of the book by focusing on a subpopulation of subplate neurons that persists through development into adulthood as layer 6b in mouse and interstitial white matter cells in human, and by discussing a transcriptionally based classification of these cells.

Complementing this section, the following section of the book with its two chapters focuses on the migration of the new-born neurons to the appropriate position within the six-layered neocortex. Laurent Nguyen and Míriam Javier-Torrent first discuss the modes of cell migration of the excitatory projection neurons and the inhibitory interneurons and dissect the differences between these two classes of cortical neurons that exist in mammals ranging from rodents to primates. The authors then concentrate on impairments of neuron migration that result in prototypic neuronal migration disorders, and discuss molecular mechanisms that regulate neuron migration and whose disturbances underlie these cortical malformations. Orly Reiner and Aditya Kshirsagar focus on LIS1, the first human gene identified and reported to be involved in neuron migration. The authors provide an in-depth analysis of the mechanisms underlying LIS1 function, its regulation, and its role in the pathophysiology of various CNS diseases.

The next section of the book addresses neural patterning and the specification of cortical regions. Madeline Lancaster and Magdalena Sutcliffe focus on early forebrain morphogenesis, specifically the patterning of the rostral neural tube and the expansion of the early forebrain neuroepithelium. They describe the role of various neural organoid models to study these processes and discuss human-specific features and their implications for microcephalic and macrocephalic disorders. The chapter by Flora Vaccarino, Soraya Scuderi, and Alexandre Jourdon covers the highly related topics of the formation of brain regions, signaling centers involved in patterning, patterning of the cortical plate and cell diversity, and the modeling of disorders of cortical development using organoids. John Rubenstein and Athéna Ypsilanti then provide an in-depth discussion of the role of transcriptional regulators in the specification of the mammalian cortex into its constituent regions and areas. They dissect how the control of gene expression that underlies cortical patterning involves a complex interplay between transcription factors, enhancers, chromatin modifiers, and epigenetics. The final chapter in this section by Elizabeth Grove on the development of the neocortical area map broadens the theme by discussing not only the mechanisms of area patterning intrinsic to the neocortex but also thalamic mechanisms of area development, as well as the conservation of patterning mechanisms among different mammalian species.

A hallmark of neocortex development and evolution is cortical folding, which occurs in many mammalian species as brain size increases, notably in the human brain. The two chapters in this section of the book address this topic. Pasko Rakic, who must be regarded as the father of the entire field covered in this book, and his colleague Jon Arellano, after providing a historical perspective, describe the main characteristics of gyrification, critically review some of the mechanisms proposed to explain cortical folding, and present their favored view on what underlies cortical folding. The second chapter by Hiroshi Kawasaki and Yohei Shinmyo focuses on the ferret as a gyrencephalic animal model of cortical folding. The authors discuss recent findings obtained in this animal model on the mechanisms underlying the development of the cerebral cortex, with an emphasis on cortical folding, and put this discussion into the broader context of common vs. species-specific mechanisms of cortical folding.

The penultimate section of the book addresses variations, disorders, and malformations of cortical development. Eva Anton, Madison Rose Glass, and Jason Stein focus on genetic variation that impacts cortical progenitor function and thereby affects human neocortex size and/or structure. The following chapter by Chris Walsh and Robert Sean Hill dissects the roles of specific genes, including SRGAP2C, ASPM, NOTCH2NL, and GPR56, in the evolution of the human neocortex and in disorders of human brain development, neurological function, and cognition. The authors also highlight the medical relevance of these types of studies. The last chapter in this section, by Silvia Cappello, Veronica Pravata, and Pierre Gressens, provides an overview of the molecular causes underlying specific cortical malformations and of their clinical features. The authors dissect at which cellular level the various cortical malformations arise.