Results and Problems in Cell Differentiation 30 Series Editors: w. Hennig, L. Nover, U. Scheer 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 cr New Haven, 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 Ihis work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publieation or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Springer-Verlag is a company in the BertelsmannSpringer publishing group. © Springer-Verlag Berlin Heidelberg 2000 Softcover reprint of the hardcover 1st edition 2000 Ihe use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Cover design: Meta Design, Berlin Iypesetting: Scientific Publishing Services (P) LId., Madras SPIN: 10681947 39/3136 -5 4 3 2 1 0 -Printed on acid-free paper Preface Our understanding of the molecular mechanisms involved in mammalian brain development remains limited. However, the last few years have wit nessed a quantum leap in our knowledge, due to technological improve ments, 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 pheno type. Nevertheless, the recent progress in genetics will allow us to contem plate, 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 develop mental biology. The purpose of the present book is to provide an overview that syn thesizes up-to-date information on selected aspects of mouse brain devel opment. 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 intro duction 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 in activation. More recently, homologous recombination has been used to se lectively 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 de velopmental 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 Cel lular Biology) reflect this increased interest and phenomenal growth. AI though 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 Introduction ................................ . 107 2 The Neocortical Pseudostratified Ventricular Epithelium .... . 109 2.1 Cytologic and Architectonic Features of the PVE ......... . 109 3 Neocortex as Outcome of Neuronogenesis in the PVE ..... . 111 3.1 The Radial Dimension of the Neocortex .............. . 113 3.2 The Tangential Dimensions of the Neocortex ........... . 114 4 The Proliferative Process Within the Murine Neocortical PVE . 115 4.1 There are Two Stages of Proliferative Activity in the PVE (Fig. 2) ............................ . 116 4.2 Neuron Production Advances in an Orderly Sequence ..... . 116 4.3 The Proliferative State of PVE Varies Across the Surface of the Neocortex ............................. . 117 4.4 The Cell Cyde in Histogenesis .................... . 117 4.5 A General Quantitative Model of Neuron Production ...... . 118 4.6 Parameters of the Model: Experiments in Mouse . . . . . . . . . . 121 4.6.1 The Number of Integer Cydes .................... . 119 4.6.2 The Q and P Fractions . . . . . . . . . . . . . . . . . . . . . . . . . . 121 4.6.3 Neuron Production Model ....................... . 123 5 Higher Order Neuronogenetic Control ............... . 125 5.1 Number of Cell Cydes Regulated by Q ............... . 126 5.2 Propagation of the Neuronogenetic Sequence Regulated by Tc . 126 5.3 Propagation of Cell Cyde Domains ................. . 127 5.3.1 Initiation of Cyde at Origin ...................... . 127 5.3.2 Propagation of Cyde Domains .................... . 129 6 The Proliferative Process and Histogenetic Specification .... . 131 6.1 Cell Number, Cell Class and Laminar Fate ............. . 131 6.2 Regional Specification Within the PVE ............... . 134 7 The PVE: A Conserved Histogenetic Specification ........ . 136 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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