Main description:

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.

Contents:

From Spontaneous to Induced Neurological Mutations: A Personal Witness of the Ascent of the Mouse Model.- 1 Introduction.- 2 Beginning: The Values and Limits of Spontaneous Mutations.- 3 Renaissance: New Opportunities and Induced Mutations.- 4 Epilogue.- References.- Mapping Genes that Modulate Mouse Brain Development: A Quantitative Genetic Approach.- 1 Introduction.- 2 Why Brain Weight and Neuron Number Matter.- 2.1 Metabolic Constraints.- 2.2 Functional Correlates.- 2.3 Insights into CNS Development.- 3 Biometric Analysis of the Size and Structure of the Mouse CNS.- 3.1 Precedents.- 3.2 A New Opportunity.- 3.3 Brain Weight is Highly Variable.- 3.4 Sex and Age Effects on Brain Weight.- 3.5 Large Differences Between Substrains.- 4 Mapping Brain Weight QTLs.- 4.1 QTLs Versus Mendelian Loci.- 4.2 Step 1: Assessing Trait Variation.- 4.3 Step 2: Estimating Heritability.- 4.4 Step 3: Phenotyping and Genotyping Members of an Experimental Cross.- 4.4.1 Phenotyping and Regression Analysis.- 4.4.2 Genotyping.- 4.5 Step 4: The Statistics of Mapping QTLs.- 4.5.1 Permutation Analysis.- 4.6 Cloning QTLs.- 4.7 Probability of Success.- 5 Neuron and Glial Cell Numbers in Adult Mice.- 5.1 The Mouse Brain Library at http://nervenet.org/mbl/mbl/html.- 5.2 Numbers of Neurons and Glial Cells in the Brain of a Mouse.- 6 Mapping QTLs that Modulate Neuron Number.- 6.1 Mapping Cell-Specific QTLs.- 6.2 The Nncl Locus.- 6.3 Mechanisms of QTL Action.- 6.4 Candidate Gene Analysis.- 7 Conclusion.- References.- Genetic Interactions During Hindbrain Segmentation in the Mouse Embryo.- 1 Introduction.- 1.1 Generation of Diversity in the Developing Nervous System.- 1.2 Segmental Organisation of the Hindbrain.- 2 Patterns of Gene Expression During Hindbrain Development.- 2.1 Hox Genes.- 2.2 Upstream Regulators of Hox Genes.- 2.3 Other Gene Families.- 3 Genetic Control of Hindbrain Patterning.- 3.1 Retinoic Acid Pathways.- 3.2 Krox20 Targets.- 3.3 Kreisler Targets.- 3.4 Hox Gene Auto- and Cross-Regulation.- 4 Mutational Analyses of Gene Function.- 4.1 Segmentation Genes.- 4.2 Segment Identity Genes.- 5 Mechanisms of Hindbrain Segmentation.- 6 Conclusions.- References.- Neurogenetic Compartments of the Mouse Diencephalon and some Characteristic Gene Expression Patterns.- 1 Introduction.- 2 Origin and Definition of Diencephalon.- 3 Diencephalic Segmentation.- 4 Diencephalic Histogenetic Differentiation.- 5 Alar Plate Domains at E12.5.- References.- Neuronogenesis and the Early Events of the Neocortical Histogenesis.- 1 Introduction.- 2 The Neocortical Pseudostratified Ventricular Epithelium.- 2.1 Cytologic and Architectonic Features of the PVE.- 3 Neocortex as Outcome of Neuronogenesis in the PVE.- 3.1 The Radial Dimension of the Neocortex.- 3.2 The Tangential Dimensions of the Neocortex.- 4 The Proliferative Process Within the Murine Neocortical PVE.- 4.1 There are Two Stages of Proliferative Activity in the PVE (Fig. 2).- 4.2 Neuron Production Advances in an Orderly Sequence.- 4.3 The Proliferative State of PVE Varies Across the Surface of the Neocortex.- 4.4 The Cell Cycle in Histogenesis.- 4.5 A General Quantitative Model of Neuron Production.- 4.6 Parameters of the Model: Experiments in Mouse.- 4.6.1 The Number of Integer Cycles.- 4.6.2 The Q and P Fractions.- 4.6.3 Neuron Production Model.- 5 Higher Order Neuronogenetic Control.- 5.1 Number of Cell Cycles Regulated by Q.- 5.2 Propagation of the Neuronogenetic Sequence Regulated by Tc.- 5.3 Propagation of Cell Cycle Domains.- 5.3.1 Initiation of Cycle at Origin.- 5.3.2 Propagation of Cycle Domains.- 6 The Proliferative Process and Histogenetic Specification.- 6.1 Cell Number, Cell Class and Laminar Fate.- 6.2 Regional Specification Within the PVE.- 7 The PVE: A Conserved Histogenetic Specification.- References.- Programmed Cell Death in Mouse Brain Development.- 1 Introduction.- 2 Conceptual Framework of Programmed Cell Death.- 3 Mechanistic Framework of Programmed Cell Death.- 4 Caspases-3 and -9 are Required for Developmental Apoptosis of Neurons.- 5 The Bcl-2 Proteins Family Has Both Proapoptotic and Antiapoptotic Effects.- 6 Apoptotic Defects in Founders and Postmitotic Neurons Have Distinct Consequences.- 7 c-Jun N-Terminal Kinases Regulate Brain Region-Specific Apoptosis.- 8 Concluding Remarks.- References.- Neurotrophic Factors: Versatile Signals for Cell-Cell Communication in the Nervous System.- 1 Introduction.- 2 The Neurotrophic Hypothesis.- 3 Neurotrophic Factors.- 4 Beyond the Neurotrophic Hypothesis.- 5 Revisiting the Neurotrophic Hypothesis with Molecular Genetics.- 6 Selective Neuronal Losses and Maturation Deficits Following Inactivation of Genes Encoding Neurotrophic Factors or Their Receptors.- 7 Neurotrophic Factors Regulate Target Invasion.- 8 BDNF as a Maturation Factor for the Cerebal Cortex.- 9 Conclusions.- References.- Growth Factor Influences on the Production and Migration of Cortical Neurons.- 1 Introduction.- 2 Trophic Factor Influences on Neurogenesis in the Ventricular Zone.- 2.1 Neurotrophins.- 2.2 Fibroblast Growth Factors.- 2.3 Insulin-Like Growth Factors.- 2.4 Trophic Collaborations.- 3 Trophic Factor Influences on Glial-Guided Radial Migration.- 4 Trophic Factor Influences on Tangential Migration.- 4.1 NT4 Produces Heterotopic Accumulations of Neurons in the MZ in vitro.- 4.2 NT4, But not BDNF, Produces Heterotopias in a TrkB-Mediated Response.- 4.3 NT4 Also Produces Heterotopic Neuronal Collections in vivo.- 5 Pathogenesis of NT4-Induced Heterotopias.- 5.1 NT4 Does Not Induce Cell Proliferation in the Marginal Zone.- 5.2 NT4-Induced Heterotopias are Composed of Marginal Zone Neurons.- 5.3 NT4-Induced Accumulation of Neurons is not at the Expense of the Subplate.- 5.4 Heterotopic Neurons are not Misplaced Cortical Plate Cells.- 5.5 Heterotopias do not Result from the Trauma of Intraventricular Injection.- 5.6 Heterotopias are not Caused by Rescue of MZ Neurons from Cell Death.- 6 What is the Source of the Excess Neurons that Form NT4-Induced Heterotopias?.- References.- Signalling from Tyrosine Kinases in the Developing Neurons and Glia of the Mammalian Brain.- 1 Introduction.- 2 Tyrosine Kinases During CNS Development.- 2.1 Growth Factors and Their Cell Surface Receptors.- 3 Phospho-Tyrosines and Their SH2 Partners.- 4 Controlling the Activity of the Ras-MAPK Pathway.- 4.1 The Players.- 4.2 MAPK: Proliferation or Differentiation?.- 4.3 Changing Adaptors for the Ras-MAPK Pathway: The Shc(s).- 5 Controlling Cell-Survival Via PI3K.- 6 The JAK/STAT Pathway: A New Route to Proliferation and Differentiation in the Brain.- 7 The Action of Phosphatases.- 8 Concluding Remarks.- References.- The Role of the p35/cdk5 Kinase in Cortical Development.- 1 Introduction.- 2 cdk5.- 3 p35 Family Members.- 4 Expression Patterns.- 5 Function of the cdk5 Kinase in Neurite Outgrowth.- 6 p35 and cdk5 Knockout Mice.- 7 p35/cdk5 and Reeler/Scrambler.- 8 Substrates.- 9 Regulation.- 10 Conclusion.- References.- The Reelin-Signaling Pathway and Mouse Cortical Development.- 1 Introduction.- 2 Overview of Early Cortical Development in Normal Mice.- 2.1 The Preplate.- 2.2 Appearance of the Cortical Plate.- 3 Cortical Phenotype in Reeler Mutant Mice.- 4 Reelin (Rein).- 4.1 The Reln Gene.- 4.2 Reln mRNA Expression During Cortical Development.- 4.3 Reln Protein.- 4.4 Studies of Reln Function.- 4.5 Reelin is Processed in vivo by a Metalloproteinase.- 4.6 Reln an Axonal Growth.- 5 Mouse Disabled1 and Scrambler/Yotari Mutations.- 6 Very Low Density Lipoprotein Receptor and Apolipoprote in E Receptor Type 2.- References.- The Subpial Granular Layer in the Developing Cerebral Cortex of Rodents.- 1 Introduction.- 2 Neuronal Populations of the Rodent Marginal Zone.- 2.1 Pioneer Neurons.- 2.2 The Subpial Granular Layer.- 2.3 Reelin-Expressing Cajal-Retzius Cells of Rodent Cortex.- 3 Possible Origin of the Rodent Subpial Granular Layer.- 4 Radial and Tangential Migration Pathways into the Cortex.- 5 Conclusions.- References.- Development of Thalamocortical Projections in Normal and Mutant Mice.- 1 Introduction.- 2 Neurogenesis and Formation of Mammalian Cortical Plate.- 3 Introduction to Development of Thalamic Nuclei.- 4 Overview of Thalamocortical Projections in the Adult Mouse.- 5 Timing and Early Pattern of Thalamic Axon Outgrowth.- 5.1 The Waiting Period.- 5.2 Invasion of the Cortex and Establishment of Laminar Termination Patterns.- 6 The Thalamocortical Pathways are Modified in Regions Where Transient Cells are Located During Development.- 6.1 The Handshake Hypothesis.- 7 Introduction to the Development of Barrel Cortex.- 7.1 Mutant Mice Provide New Insights into Developmental Mechanisms.- 8 Axonal Pathfinding at the Cortico-Striatal Junction in Tbr-1, Gbx-2 and Pax-6 KO Mice.- 8.1 The reeler Mouse.- 8.1.1 The reeler Phenotype.- 8.1.2 The reeler Mutant Mouse as a Model System to Explore Mechanisms of Thalamocortical Development.- 8.2 The L1 KO Mouse.- 8.2.1 Possible Inhibitory Factory in and Around the Internal Capsule.- 9 Mutants with Disturbances in Thalamocortical Interactions.- 9.1 Barrel Formation in reeler Mouse.- 9.2 The Barrelless Mouse.- 9.2.1 The Barrelless Phenotype.- 9.2.2 Lack of Formation and Stabilisation of Barrel Patterns in the Mutant.- 9.2.3 Similar Areal Differences in Thalamocortical Innervation Patterns in Normal and Barrelless Mice.- 9.3 The MAO-A KO Mouse.- 9.4 The NMDA Receptor KO Mouse: Role of Activity in Barrel Formation.- 9.5 A Specific Postsynaptic Defect in Barrel Formation Identified in PLC-?1 Knockout mice.- 9.6 The GAP-43 KO Mouse.- 9.7 Overview of Mutant Mice with Barrelless Phenotypes.- 10 Mutations Indirectly Affecting Thalamocortical Development.- 10.1 Thalamocortical Topography in Anophthalmic Mutants and After Early Binocular Enucleation.- 10.2 Altered Thalamocortical Topography in Albinism and After Early Monocular Enucleation.- 10.3 Extranumery Vibrissae.- 11 Conclusions.- References.