With the enormous development of human and mouse genomics and the availability of a variety of transgenic techniques, the mouse has become the most widely used animal for basic studies of brain development and as a model for human developmental disorders. The topics are addressed using a diversity of techniques, from genetic, biochemical and cell biological to morphological and functional. The conceptual approaches also provide a framework for studies of other problems and point the way towards future research.

Klappentext

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.

Inhalt

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?.-…