Results and Problems in Cell Differentiation

Series Editors: w. Hennig, L. Nover, U. Scheer 30

Springer Berlin Heidelberg New York Barcelona Hong Kong London Milan Paris Singapore Tokyo

Andre M. Goffinet . Pasko Rakic (Eds.)

Mouse Brain Development

With 69 Figures

Springer

ANDRE M. GOFFINET

Neurobiology Unit University of Namur Medical School 61, rue de Bruxelles B-5000 Namur Belgium

PASKO RAKIC

Section of Neurobiology Yale University School of Medicine 333, Cedar Street New Haven, cr 06510

ISSN 0080-1844 ISBN 978-3-642-53684-7

Library of Congress Cataloging-in-Pulication Data

Mouse brain development / Andre M. Goffinet, Pasko Rakie (eds.) p. cm. -- (Results and Problems in Cell Differentiation; 30)

Includes bibliographieal references. ISBN 978-3-642-53684-7 ISBN 978-3-540-48002-0 (eBook) DOI 10.1007/978-3-540-48002-0

1. Developmental neurobiology. 2. Mice as laboratory animals. I. Goffinet, A. 11. Rakic, Pasko, 1933- 11. Series.

QP363.5 .M68 2000 573.8'619353--dc21

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Preface

Our understanding of the molecular mechanisms involved in mammalian brain development remains limited. However, the last few years have wit­nessed a quantum leap in our knowledge, due to technological improve­ments, particularly in molecular genetics. Despite this progress, the available body of data remains mostly phenomenological and reveals very little about the grammar that organizes the molecular dictionary to articulate a pheno­type. Nevertheless, the recent progress in genetics will allow us to contem­plate, for the first time, the integration of observation into a coherent view of brain development. Clearly, this may be a major challenge for the next century, and arguably is the most important task of contemporary develop­mental biology.

The purpose of the present book is to provide an overview that syn­thesizes up-to-date information on selected aspects of mouse brain devel­opment. Given the format, it was not possible to cover all aspects of brain development, and many important subjects are missing. The selected themes are, to a certain extent, subjective and reflect the interests of the contributing authors. Examples of major themes that are not covered are peripheral nervous system development, including myelination, the development of the hippocampus and several other CNS structures, as well as the developmental function of some important morphoregulatory molecules.

Although the use of the mouse as an animal model for studies of brain development is not new and was pioneered in the 1960s, mice did not become the favored animal model for studying brain development until the intro­duction of transgenic techniques (see Chap. 1 for historical perspectives). During the last few years, a number of new mutations have been generated. Initially, mutations were induced more or less randomly by transgenic in­activation. More recently, homologous recombination has been used to se­lectively inactivate specific genes. No doubt many mutants are available that have not yet been published, and it can be safely predicted that thousands will be generated during the next decade. In parallel, a large number of human genetic diseases that affect brain development are being characterized in molecular terms, and the pathophysiological understanding of each of them will require development studies in transgenic mice. Moreover, the validation of the Cre-IoxP and Tet-on/off systems will allow modification of the temporal and cellular specificity of expression of any given form of a

VI Preface

selected gene: the task ahead seems almost infinite! Thus, although basic developmental questions will remain to be tackled in comparatively simple models such as invertebrates (Drosophila, C. elegans) or in vertebrates such as Xenopus or zebrafish, the mouse will take central stage in the elucidation of brain development. However, the work in other mammals will also remain essential at some stage, particularly for developmental studies on the highly evolved structures like the cerebral cortex. The larger mammals such as carnivores and primates will probably be reserved to address specific de­velopmental questions downstream of developmental genetic work carried out in simpler models and mice.

For all these reasons, the field of mouse developmental neurobiology will probably expand even further the next decade. For example, at many research institutions, the population of mice has quadrupled in the last 10 years, largely due to an increased demand for maintaining colonies of transgenic mice. The recently created International Behavioral and Neural Genetics Society (IBANGS) as well as the proliferation of international symposia, discussion forums on the Internet (e.g. hUp://www.bres-forum), and special issues in journals (e.g., Brain Research, Cerebral Cortex, Molecular and Cel­lular Biology) reflect this increased interest and phenomenal growth. AI­though various publications and web sites keep researchers informed, the problem of maintaining as well as cataloging the complex and uncoordinated nomenclature is formidable.

Given the gaps in the present book, which are mentioned above, 10 years from now the idea of writing a single volume on mouse brain development may sound unrealistic. So, this book is among the first and perhaps the last of such enterprises, and therefore may become a collector's item. However, before it is auctioned at Sotheby's, we hope it will find some use in the growing scientific community of dedicated colleagues who are working in this field. We wish to thank all of the contributors for taking a significant part of their time to help make this book possible. We also wish to thank the staff of Springer Verlag, particularly Ursula Gramm, for their understanding with some inevitable practical problems and for their most competent assistance.

Andre M. Goffinet and Pasko Rakic

Contents

From Spontaneous to Induced Neurological Mutations: A Personal Witness of the Ascent of the Mouse Model Pasko Rakic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1 2 Beginning: The Values and Limits of Spontaneous Mutations . .. 3 3 Renaissance: New Opportunities and Induced Mutations. . . . .. 9 4 Epilogue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 14

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 15

Mapping Genes that Modulate Mouse Brain Development: A Quantitative Genetic Approach Robert W. Williams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 21

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 21 2 Why Brain Weight and Neuron Number Matter . . . . . . . . . .. 22 2.1 Metabolie Constraints . . . . . . . . . . . . . . . . . . . . . . . . . . .. 22 2.2 Functional Correlates . . . . . . . . . . . . . . . . . . . . . . . . . . .. 22 2.3 Insights into CNS Development. . . . . . . . . . . . . . . . . . . . .. 23 3 Biometrie Analysis of the Size and Structure of the Mouse CNS. 24 3.1 Precedents................................... 24 3.2 A New Opportunity . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 24 3.3 Brain Weight is Highly Variable . . . . . . . . . . . . . . . . . . . .. 25 3.4 Sex and Age Effects on Brain Weight . . . . . . . . . . . . . . . . .. 25 3.5 Large Differences Between Substrains . . . . . . . . . . . . . . . . .. 27 4 Mapping Brain Weight QTLs . . . . . . . . . . . . . . . . . . . . . .. 27 4.1 QTLs Versus Mendelian Lod . . . . . . . . . . . . . . . . . . . . . .. 27 4.2 Step 1: Assessing Trait Variation. . . . . . . . . . . . . . . . . . . .. 27 4.3 Step 2: Estimating Heritability ...................... 29 4.4 Step 3: Phenotyping and Genotyping Members

of an Experimental Cross ......................... 30 4.4.1 Phenotyping and Regression Analysis . . . . . . . . . . . . . . . . .. 31 4.4.2 Genotyping. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 33 4.5 Step 4: The Statisties of Mapping QTLs . . . . . . . . . . . . . . . .. 34

VIII Contents

4.5.1 Permutation Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . .. 36 4.6 Cloning QTLs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 38 4.7 Probability of Success . . . . . . . . . . . . . . . . . . . . . . . . . . .. 38 5 Neuron and Glial Cell Numbers in Adult Mice . . . . . . . . . . .. 39 5.1 The Mouse Brain Library at http://nervenet.orglmbllmbllhtml .. 40 5.2 Numbers of Neurons and Glial Cells in the Brain of a Mouse. .. 41 6 Mapping QTLs that Modulate Neuron Number . . . . . . . . . . .. 42 6.1 Mapping Cell-Specific QTLs . . . . . . . . . . . . . . . . . . . . . . .. 42 6.2 The Nncl Locus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 42 6.3 Mechanisms of QTL Action . . . . . . . . . . . . . . . . . . . . . . .. 43 6.4 Candidate Gene Analysis . . . . . . . . . . . . . . . . . . . . . . . . .. 43 7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 44

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 44

Genetic Interactions During Hindbrain Segmentation in the Mouse Embryo Paul A. Trainor, Miguel Manzanares, and Robb Krumlauf 51

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 51 1.1 Generation of Diversity in the Developing Nervous

System ........... . . . . . . . . . . . . . . . . . . . . . . . . .. 51 1.2 Segmental Organisation of the Hindbrain ............... 53 2 Patterns of Gene Expression During Hindbrain Development . .. 55 2.1 Hox Genes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 55 2.2 Upstream Regulators of Hox Genes ...... . . . . . . . . . . . .. 58 2.3 Other Gene Families . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 59 3 Genetic Control of Hindbrain Patterning . . . . . . . . . . . . . . .. 61 3.1 Retinoic Acid Pathways . . . . . . . . . . . . . . . . . . . . . . . . . .. 62 3.2 Krox20 Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 64 3.3 Kreisler Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 66 3.4 Hox Gene Auto- and Cross-Regulation . . . . . . . . . . . . . . . .. 67 4 Mutational Analyses of Gene Function . . . . . . . . . . . . . . . .. 69 4.1 Segmentation Genes. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 69 4.2 Segment Identity Genes. . . . . . . . . . . . . . . . . . . . . . . . . .. 72 5 Mechanisms of Hindbrain Segmentation . . . . . . . . . . . . . . .. 76 6 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 77 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 78

Contents IX

Neurogenetic Compartments of the Mouse Diencephalon and some Characteristic Gene Expression Patterns Salvador Martinez and Luis Puelles . . . . . . . . . . . . . . . . . . . . . .. 91

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 91 2 Origin and Definition of Diencephalon . . . . . . . . . . . . . . . .. 94 3 Diencephalic Segmentation. . . . . . . . . . . . . . . . . . . . . . . .. 96 4 Diencephalic Histogenetic Differentiation ............... 98 5 Alar Plate Domains at E12.5 ...................... " 99

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 103

Neuronogenesis and the Early Events of the Neocortical Histogenesis V. S. Caviness, Ir., T. Takahashi, and R. S. Nowakowski . . . . . . . .. 107

1 2 2.1 3 3.1 3.2 4 4.1

4.2 4.3

4.4 4.5 4.6 4.6.1 4.6.2 4.6.3 5 5.1 5.2 5.3 5.3.1 5.3.2 6 6.1 6.2 7

Introduction ................................ . The Neocortical Pseudostratified Ventricular Epithelium .... . Cytologic and Architectonic Features of the PVE ......... . Neocortex as Outcome of Neuronogenesis in the PVE ..... . The Radial Dimension of the Neocortex .............. . The Tangential Dimensions of the Neocortex ........... . The Proliferative Process Within the Murine Neocortical PVE . There are Two Stages of Proliferative Activity in the PVE (Fig. 2) ............................ . Neuron Production Advances in an Orderly Sequence ..... . The Proliferative State of PVE Varies Across the Surface of the Neocortex ............................. . The Cell Cyde in Histogenesis .................... . A General Quantitative Model of Neuron Production ...... . Parameters of the Model: Experiments in Mouse . . . . . . . . . . The Number of Integer Cydes .................... . The Q and P Fractions . . . . . . . . . . . . . . . . . . . . . . . . . . Neuron Production Model ....................... . Higher Order Neuronogenetic Control ............... . Number of Cell Cydes Regulated by Q ............... . Propagation of the Neuronogenetic Sequence Regulated by Tc . Propagation of Cell Cyde Domains ................. . Initiation of Cyde at Origin ...................... . Propagation of Cyde Domains .................... . The Proliferative Process and Histogenetic Specification .... . Cell Number, Cell Class and Laminar Fate ............. . Regional Specification Within the PVE ............... . The PVE: A Conserved Histogenetic Specification ........ . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

107 109 109 111 113 114 115

116 116

117 117 118 121 119 121 123 125 126 126 127 127 129 131 131 134 136 138

x Contents

Programmed Cell Death in Mouse Brain Development Chia-Yi Kuan, Richard A. Flavell, and Pasko Rakic . . . . . . . . . . .. 145

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 145 2 Conceptual Framework of Programmed Cell Death ........ 145 3 Mechanistic Framework of Programmed Cell Death . . . . . . .. 147 4 Caspases-3 and -9 are Required for Developmental Apoptosis

of Neurons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 148 5 The Bcl-2 Proteins Family Has Both Proapoptotic

and Antiapoptotic Effects ........................ 151 6 Apoptotic Defects in Founders and Postmitotic Neurons

Have Distinct Consequences . . . . . . . . . . . . . . . . . . . . . .. 154 7 c-Jun N-Terminal Kinases Regulate Brain Region-Specific

Apoptosis .................................. 156 8 Concluding Remarks ........................... 158 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 160

Neurotrophic Factors: Versatile Signals for Cell-Cell Communication in the N ervous System Carlos F. Ibafiez . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 163

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 163 2 The Neurotrophic Hypothesis . . . . . . . . . . . . . . . . . . . . .. 164 3 Neurotrophic Factors . . . . . . . . . . . . . . . . . . . . . . . . . .. 167 4 Beyond the Neurotrophic Hypothesis . . . . . . . . . . . . . . . .. 168 5 Revisiting the Neurotrophic Hypothesis with Molecular Genetics. 171 6 Selective Neuronal Losses and Maturation Deficits Following

Inactivation of Genes Encoding Neurotrophic Factors or Their Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 173

7 Neurotrophic Factors Regulate Target Invasion. . . . . . . . . .. 178 8 BDNF as a Maturation Factor for the Cerebal Cortex. . . . . .. 181 9 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 184

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 184

Growth Factor Influences on the Production and Migration of Cortical Neurons Janice E. Brunstrom and Alan L. Pearlman . . . . . . . . . . . . . . . .. 189

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 189 2 Trophic Factor Infiuences on Neurogenesis

in the Ventricular Zone. . . . . . . . . . . . . . . . . . . . . . . . .. 190 2.1 Neurotrophins................................ 190 2.2 Fibroblast Growth Factors . . . . . . . . . . . . . . . . . . . . . . .. 191

Contents XI

2.3 Insulin-Like Growth Factors . . . . . . . . . . . . . . . . . . . . . .. 194 2.4 Trophic Collaborations . . . . . . . . . . . . . . . . . . . . . . . . .. 195 3 Trophic Factor Influences on Glial-Guided Radial Migration .. 196 4 Trophic Factor Influences on Tangential Migration . . . . . . .. 197 4.1 NT4 Pro duces Heterotopic Accumulations of Neurons

in the MZ in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 198 4.2 NT4, But not BDNF, Produces Heterotopias

in a TrkB-Mediated Response. . . . . . . . . . . . . . . . . . . . .. 198 4.3 NT4 Also Produces Heterotopic Neuronal Collections in vivo.. 200 5 Pathogenesis of NT4-Induced Heterotopias ............. 200 5.1 NT4 Does Not Induce Cell Proliferation in the Marginal Zone. 201 5.2 NT4-Induced Heterotopias are Composed of Marginal

Zone Neurons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 202 5.3 NT4-Induced Accumulation of Neurons is not at the Expense

of the Subplate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 202 5.4 Heterotopic Neurons are not Misplaced Cortical Plate Cells . .. 202 5.5 Heterotopias do not Result from the Trauma

of Intraventricular Injection . . . . . . . . . . . . . . . . . . . . . .. 203 5.6 Heterotopias are not Caused by Rescue of MZ Neurons

from Cell Death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 203 6 What is the Source of the Excess Neurons that

Form NT4-Induced Heterotopias? .... . . . . . . . . . . . . . .. 204 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 207

Signalling from Tyrosine Kinases in the Developing Neurons and Glia of the Mammalian Brain Elena Cattaneo and Massimo Gulisano . . . . . . . . . . . . . . . . . . .. 217

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .". 217 2 Tyrosine Kinases During CNS Development . . . . . . . . . . . .. 218 2.1 Growth Factors and Their Cell Surface Receptors ......... 218 3 Phospho-Tyrosines and Their SH2 Partners. . . . . . . . . . . .. 221 4 Controlling the Activity of the Ras-MAPK Pathway . . . . . . .. 223 4.1 The Players ................................. 223 4.2 MAPK: Proliferation or Differentiation? . . . . . . . . . . . . . . .. 225 4.3 Changing Adaptors for the Ras-MAPK Pathway: The Shc(s) . .. 226 5 Controlling Cell-Survival Via PI3K . . . . . . . . . . . . . . . . . .. 227 6 The JAK/STAT Pathway: A New Route to Proliferation

and Differentiation in the Brain .................... 229 7 The Action of Phosphatases . . . . . . . . . . . . . . . . . . . . . .. 232 8 Concluding Remarks ........................... 233

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 234

XII Contents

The Role of the p35/cdk5 Kinase in Cortical Development Yong T. Kwon and Li-Huei Tsai . . . . . . . . . . . . . . . . . . . . . . .. 241

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 241 2 cdk5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 241 3 p35 Family Members ........................... 242 4 Expression Patterns . . . . . . . . . . . . . . . . . . . . . . . . . . .. 243 5 Function of the cdk5 Kinase in Neurite Outgrowth ........ 243 6 p35 and cdk5 Knockout Mice . . . . . . . . . . . . . . . . . . . . .. 244 7 p35/cdk5 and ReelerlScrambler . . . . . . . . . . . . . . . . . . . .. 247 8 Substrates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 248 9 Regulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 248 10 Conclusion.................................. 249

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 251

The Reelin-Signaling Pathway and Mouse Cortical Development Isabelle Bar, Catherine Lambert de Rouvroit, and Andre M. Goffinet . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 255

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 255 2 Overview of Early Cortical Development in Normal Mice .... 255 2.1 The Preplate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 257 2.2 Appearance of the Cortical Plate . . . . . . . . . . . . . . . . . . .. 257 3 Cortical Phenotype in Reeler Mutant Mice . . . . . . . . . . . . .. 258 4 Reelin (ReIn) ................................ 262 4.1 The ReIn Gene ............................... 262 4.2 ReIn mRNA Expression During Cortical Development ...... 265 4.3 ReIn Pro tein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 265 4.4 Studies of ReIn Function . . . . . . . . . . . . . . . . . . . . . . . .. 266 4.5 Reelin is Processed in vivo by a Metalloproteinase. . . . . . . .. 266 4.6 ReIn an Axonal Growth . . . . . . . . . . . . . . . . . . . . . . . . .. 267 5 Mouse Disabledl and Scrambler/Yotari Mutations . . . . . . . .. 268 6 Very Low Density Lipoprotein Receptor

and Apolipoprote in E Receptor Type 2 ............... 271 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 274

The Subpial Granular Layer in the Developing Cerebral Cortex of Rodents Gundela Meyer, Rafael Castro, Jose Miguel Soria, and Alfonso Fairen 277

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 277 2 Neuronal Populations of the Rodent Marginal Zone. . . . . . .. 279 2.1 Pioneer Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 279

Contents XIII

2.2 The Subpial Granular Layer . . . . . . . . . . . . . . . . . . . . . .. 281 2.3 Reelin-Expressing Cajal-Retzius Cells of Rodent Cortex. . . . .. 284 3 Possible Origin of the Rodent Subpial Granular Layer ...... 285 4 Radial and Tangential Migration Pathways into the Cortex ... 286 5 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 288

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 289

Development of Thalamocortical Projections in Normal and Mutant Mice Zoltan Molnar and Anthony J. Hannan ................... 293

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 293 2 Neurogenesis and Formation of Mammalian Cortical Plate ... 294 3 Introduction to Development of Thalamic Nuclei ......... 295 4 Overview of Thalamocortical Projections in the Adult Mouse .. 296 5 Timing and Early Pattern of Thalamic Axon Outgrowth . . . .. 296 5.1 The Waiting Period . . . . . . . . . . . . . . . . . . . . . . . . . . .. 298 5.2 Invasion of the Cortex and Establishment of Laminar

Termination Patterns .. . . . . . . . . . . . . . . . . . . . . . . . .. 299 6 The Thalamocortical Pathways are Modified in Regions

Where Transient Cells are Located During Development . . . .. 301 6.1 The Handshake Hypothesis ....................... 301 7 Introduction to the Development of Barrel Cortex ....... " 302 7.1 Mutant Mice Provide New Insights into Developmental

Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 303 8 Axonal Pathfinding at the Cortico-Striatal Junction

in Tbr-l, Gbx-2 and Pax-6 KO Mice . . . . . . . . . . . . . . . . .. 304 8.1 The reeler Mouse. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 305 8.1.1 The reeler Phenotype . . . . . . . . . . . . . . . . . . . . . . . . . .. 305 8.1.2 The reeler Mutant Mouse as a Model System to Explore

Mechanisms of Thalamocortical Development ........... 305 8.2 The LI KO Mouse . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 309 8.2.1 Possible Inhibitory Factory in and Around the Internal

Capsule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 309 9 Mutants with Disturbances in Thalamocortical Interactions . .. 310 9.1 Barrel Formation in reeler Mouse ................... 312 9.2 The Barrelless Mouse . . . . . . . . . . . . . . . . . . . . . . . . . .. 313 9.2.1 The Barrelless Phenotype . . . . . . . . . . . . . . . . . . . . . . . .. 313 9.2.2 Lack of Formation and Stabilisation of Barrel Patterns

in the Mutant. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 314 9.2.3 Similar Areal Differences in Thalamocortical Innervation

Patterns in Normal and Barrelless Mice. . . . . . . . . . . . . . .. 314 9.3 The MAO-A KO Mouse. . . . . . . . . . . . . . . . . . . . . . . . .. 315

XIV Contents

9.4 The NMDA Receptor KO Mouse: Role of Activity in Barrel Formation. . . . . . . . . . . . . . . . . . . . . . . . . . .. 316

9.5 A Specific Postsynaptic Defect in Barrel Formation Identified in PLC-ß1 Knockout mice. . . . . . . . . . . . . . . . . . . . . . .. 317

9.6 The GAP-43 KO Mouse. . . . . . . . . . . . . . . . . . . . . . . . .. 318 9.7 Overview of Mutant Mice with Barrelless Phenotypes ..... " 319 10 Mutations Indirectly Affecting Thalamocortical Development .. 319 10.1 Thalamocortical Topography in Anophthalmic Mutants

and After Early Binocular Enucleation ................ 320 10.2 Altered Thalamocortical Topography in Albinism

and After Early Monocular Enucleation. . . . . . . . . . . . . . .. 321 10.3 Extranumery Vibrissae . . . . . . . . . . . . . . . . . . . . . . . . .. 322 11 Conclusions................................. 322

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 323

Subject Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 333