André M. Goffinet

DIRECT BINDING OF REELIN TO VLDL RECEPTOR AND APOE RECEPTOR 2 INDUCES TYROSINE PHOSPHORYLATION OF DISABLED-1 AND MODULATES TAU PHOSPHORYLATION

The large extracellular matrix protein Reelin is produced by Cajal-Retzius neurons in specific regions of the developing brain, where it controls neuronal migration and positioning. Genetic evidence suggests that interpretation of the Reelin signal by migrating neurons involves two neuronal cell surface proteins, the very low density lipoprotein receptor (VLDLR) and the apoE receptor 2 (ApoER2) as well as a cytosolic adaptor protein, Disabled-1 (Dab1). We show that Reelin binds directly and specifically to the ectodomains of VLDLR and ApoER2 in vitro and that blockade of VLDLR and ApoER2 correlates with loss of Reelin-induced tyrosine phosphorylation of Disabled-1 in cultured primary embryonic neurons. Furthermore, mice that lack either Reelin or both VLDLR and ApoER2 exhibit hyperphosphorylation of the microtubule-stabilizing protein tau. Taken together, these findings suggest that Reelin acts via VLDLR and ApoER2 to regulate Disabled-1 tyrosine phosphorylation and microtubule function in neurons.

Tbr1 Regulates Differentiation of the Preplate and Layer 6

During corticogenesis, early-born neurons of the preplate and layer 6 are important for guiding subsequent neuronal migrations and axonal projections. Tbr1 is a putative transcription factor that is highly expressed in glutamatergic early-born cortical neurons. In Tbr1-deficient mice, these early-born neurons had molecular and functional defects. Cajal-Retzius cells expressed decreased levels of Reelin, resulting in a reeler-like cortical migration disorder. Impaired subplate differentiation was associated with ectopic projection of thalamocortical fibers into the basal telencephalon. Layer 6 defects contributed to errors in the thalamocortical, corticothalamic, and callosal projections. These results show that Tbr1 is a common genetic determinant for the differentiation of early-born glutamatergic neocortical neurons and provide insights into the functions of these neurons as regulators of cortical development.

Reelin and brain development

Over the last 50 years, the reeler mutant mouse has become an important model for studying normal and abnormal development in the cerebral cortex and other regions of the brain. However, we are only just beginning to understand the actions of reelin — the protein that is affected by the reeler mutation — at the molecular and cellular level. This review discusses the most recent advances in this research field, and considers the merits of the various models that have been put forward to explain how reelin works.

ABERRANT SPLICING OF A MOUSE DISABLED HOMOLOG, MDAB1, IN THE SCRAMBLER MOUSE

Although accurate long-distance neuronal migration is a cardinal feature of cerebral cortical development, little is known about control of this migration. The scrambler (scm) mouse shows abnormal cortical lamination that is indistinguishable from reeler. Genetic and physical mapping of scm identified yeast artificial chromosomes containing an exon of mdab1, a homolog of Drosophila disabled, which encodes a phosphoprotein that binds nonreceptor tyrosine kinases. mdab1 transcripts showed abnormal splicing in scm homozygotes, with 1.5 kb of intracisternal A particle retrotransposon sequence inserted into the mdab1 coding region in antisense orientation, producing a mutated and truncated predicted protein. Therefore, mdab1 is most likely the scm gene, thus implicating nonreceptor tyrosine kinases in neuronal migration and lamination in developing cerebral cortex.

Events Governing Organization of Postmigratory Neurons - Studies On Brain-development in Normal and Reeler Mice

The purpose of the present work is to examine some of the mechanisms responsible for the early architectonic differentiation of the central nervous system, as well as for the abnormal development which occurs in certain hereditary malformations. In order to approach these questions, the embryonic development of the cerebral cortex, the cerebellum, the inferior olivary complex and the facial nerve nucleus has been studied in normal and reeler mutant mice, using morphological methods. The adult reeler phenotype is characterized not only by extreme laminar abnormalities of cell positioning in the telencephalic and cerebellar cortices, but also by relatively less extreme, though distinct abnormal architectonics in non-cortical structures such as the inferior olive and the facial nerve nucleus. Study of the embryonic development of these structures reveals that neurons are generated at the normal time and migrate along normal pathways. Moreover, the processes of directional axonal growth, differentiation of class specific features of neurons and glia, and synaptogenesis appear similar in both genotypes and are probably not directly affected by the reeler mutation. However, in all instances, the early architectonic organization achieved by reeler cortical, Purkinje, olivary or facial neurons at the end of their migration is consistently less regular than in normal embryos. In addition, these anomalies become amplified during the later developmental period. This evidence for the early appearance of abnormalities in reeler embryos indicates that the disposition of neurons at maturity cannot be exclusively regarded as secondary to the maturation of cells, neurites and connections, but is contingent upon a specific mechanism. One may infer that the presence of a normal allele at the reeler locus is necessary for the normal completion of this histogenetic step, which consequently is submitted to genetic control. Although the factor(s) responsible for the stable configuration of the early architectonics is unknown, various hypotheses are considered. Several lines of evidence are presented which argue against a major role being played by diffusible factors, mesodermal components and afferent fiber systems. Two mechanisms are considered particularly worth evaluating: (1) a diminution of relative adhesivity between neurons and radial glial fibers at the end of migration, and (2) a stabilization of neuronal configuration by selective recognition-adhesion among postmigratory neurons. The reeler gene could, directly or indirectly, affect these cell-cell interactions.(ABSTRACT TRUNCATED AT 400 WORDS)

Protocadherin Celsr3 is crucial in axonal tract development

In the embryonic CNS, the development of axonal tracts is required for the formation of connections and is regulated by multiple genetic and microenvironmental factors. Here we show that mice with inactivation of Celsr3, an ortholog of Drosophila melanogaster flamingo (fmi; also known as starry night, stan) that encodes a seven-pass protocadherin, have marked, selective anomalies of several major axonal fascicles, implicating protocadherins in axonal development in the mammalian CNS for the first time. In flies, fmi controls planar cell polarity (PCP) in a frizzled-dependent but wingless-independent manner. The neural phenotype in Celsr3 mutant mice is similar to that caused by inactivation of Fzd3, a member of the frizzled family. Celsr3 and Fzd3 are expressed together during brain development and may act in synergy. Thus, a genetic pathway analogous to the one that controls PCP is key in the development of the axonal blueprint.

Reelin mRNA expression during mouse brain development

Using in situ hybridization, expression of the mRNA for reelin, the gene most probably responsible for the reeler trait, was studied during mouse brain development. from embryonic day 13 to maturity. The highest level of expression was found in Cajal‐Retzius neurons, while a high signal was also seen in the olfactory bulb, the external granular layer of the cerebellum and, particularly at early developmental stages, in hypothalamic differentiation fields, tectum and spinal cord. A moderate to low level of expression was found in the septa1 area, striatal fields, habenular nuclei, some thalamic nuclei, particularly the lateral geniculate, the retina and some nuclei of the reticular formation in the central field of the medulla. Paradoxically, no reelin expression was detected in radial glial cells, the cortical plate, Purkinje cells, inferior olivary neurons and many other areas that are characteristically abnormal in reeler mutant mice. Together with other preliminary studies, the present observations suggest that the action of reelin is indirect, possibly mediated by the extracellular matrix. Most of the data can be explained by supposing that reelin is a cell‐repulsive molecule which prevents migrating neurons from invading reelin‐rich areas, and thus facilitates the deployment of radial glial cell processes and the formation of early architectonic patterns.

Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus

Ependymal cells form the epithelial lining of cerebral ventricles. Their apical surface is covered by cilia that beat in a coordinated fashion to facilitate circulation of the cerebrospinal fluid (CSF). The genetic factors that govern the development and function of ependymal cilia remain poorly understood. We found that the planar cell polarity cadherins Celsr2 and Celsr3 control these processes. In Celsr2-deficient mice, the development and planar organization of ependymal cilia are compromised, leading to defective CSF dynamics and hydrocephalus. In Celsr2 and Celsr3 double mutant ependyma, ciliogenesis is markedly impaired, resulting in lethal hydrocephalus. The membrane distribution of Vangl2 and Fzd3, two key planar cell polarity proteins, was disturbed in Celsr2 mutants, and even more so in Celsr2 and Celsr3 double mutants. Our findings suggest that planar cell polarity signaling is involved in ependymal cilia development and in the pathophysiology of hydrocephalus, with possible implications in other ciliopathies.

The Reeler Mouse as a Model of Brain Development

Give us 5 minutes and we will show you the best book to read today. This is it, the the reeler mouse as a model of brain development 1st edition reprint that will be your best choice for better reading book. Your five times will not spend wasted by reading this website. You can take the book as a source to make better concept. Referring the books that can be situated with your needs is sometime difficult. But here, this is so easy. You can find the best thing of book that you can read.1 Brain Development in Normal and reeler Mice: The Phenotype.- 1.1 Some Introductory Background.- 1.2 The Early Development of the Normal Cerebral Cortex.- 1.2.1 Orientation of Mitoses in the Ventricular Zone.- 1.2.2 The Preplate.- 1.2.3 The Early Marginal Zone.- 1.2.4 The Appearance of the Cortical Plate.- 1.3 Early Cortical Histogenesis in reeler Mutant Mice.- 1.4 The reeler Cerebellum.- 1.5 The reeler Inferior Olivary Complex.- 1.6 The Facial Nerve Nucleus and Other Targets.- 1.6.1 Other Targets of the reeler Gene.- 1.7 ECM Components and Cortical Development.- 1.7.1 ECM and Fiber Growth.- 1.7.2 Integrins.- 2 Genetics of reeler and Genomics of reelin.- 2.1 Genetics and the Various Alleles of reeler.- 2.1.1 Rat reeler-like Mutations.- 2.1.2 Other Mouse Mutations with a reeler-like Phenotype.- 2.2 Mapping of reeler and Cloning of reelin.- 2.2.1 Mapping.- 2.2.2 The reelin cDNA.- 2.3 Genomic Organization of the reelin Gene.- 2.3.1 Alternative Splicing of the reelin Gene.- 2.3.1.1 Alternative Use of a Six Base Pair Microexon.- 2.3.1.2 Alternative Polyadenylation.- 2.3.2 The Promoter Region.- 2.3.3 Clues to the Possible Origin of the reelin Repeats?.- 3 Topography and Cellular Localization of reelin mRNA and Protein Expression During Brain Development.- 3.1 reelin mRNA Expression During Development.- 3.2 Study of Reelin Protein Expression Using Antibodies to Reelin.- 3.2.1 Antireelin Antibodies.- 3.2.2 Reelin Protein Expression During Mouse Brain and Human Cortical Development.- 3.2.3 Studies of Reelin Function Using Antireelin Antibodies.- 3.2.4 Is the Reelin Protein Processed in the Embryonic Mouse Brain?.- 3.3 Some Questions Raised by the Studies of Reelin Expression.- 3.3.1 Cajal-Retzius Cells and Other Reelin-positive Cells in the Developing Cortical Marginal Zone.- 3.3.2 Does Reelin Act on Postmigratory Neurons, Radial Glia or Both?.- 3.3.3 Reelin Expression is Poorly Correlated With the reeler Phenotype.- 3.3.4 Reelin as a Repulsive, Extracellular Matrix-Expanding Molecule?.- 3.3.5 Reelin and Axonal Growth.- 4 The reeler Mutation and Brain Evolution.- 4.1 The Evolution of Brain Development: A New Theme?.- 4.2 Comparative Data on Cell Migration, Maturation, Synaptogenesis And Neurogenesis.- 4.3 Comparison of Cortical Plate Development in Emys and Lacerta.- 4.3.1 Biological Mechanisms Involved in the Histogenesis of the Cortical Plate.- 4.3.2 Evolutionary Considerations.- 4.4 Reelin and a Model of Cortical Evolution.- 5 A Model of Cortical Development Inspired by reeler: Facts and Hypotheses.- 5.1 Early Hypotheses on the Actions of the reeler Gene on the Developing Brain.- 5.1.1 Reeler and Cell Interaction/Adhesion.- 5.1.2 The Action of the reeler Gene is Intrinsic to the Neuroepithelium.- 5.1.3 Reeler Phenotype and Radial Glial Fibers.- 5.2 Mouse Disabledl and the Scrambler/yotari Mutations.- 5.3 Cyclin-Dependent Protein Kinase 5 and its Activator p35: Definition of a New Step in Mammalian Cortical Development.- 5.4 Reeler-Type Malformations and Human Neuropathology.- References.

A panel of monoclonal antibodies against reelin, the extracellular matrix protein defective in reeler mutant mice

Reelin, the extracellular matrix protein defective in reeler mutant mice, plays a key role during brain development. We therefore raised antibodies directed against various reelin epitopes in order to facilitate biochemical and cell biological studies of this important molecule. Homozygous reeler mice with a large deletion of most of the reelin gene were immunized with fusion proteins and carrier-coupled peptides corresponding to parts of the reelin sequence. Monoclonal antibodies were produced using classical procedures, screened using ELISA and-or western blot prepared with the antigen, and tested by immunohistochemistry and immunoprecipitation assays to detect endogenous reelin. The labeling of Cajal-Retzius cells in the embryonic mouse telencephalon was selected as criterion for positivity in immunohistochemistry. A total of 11 monoclonal antibodies were obtained, providing useful additions to the widely used antibody CR-50. Five are directed against the N-terminal part of reelin, among which three recognize the region that has significant similarity with F-spondin, and two are specific for hinge region located downstream from the F-spondin similarity region and upstream from the reelin repeats. Six antibodies are directed against the C-terminal part of reelin, among which one anti-peptide antibody recognizes the highly basic C-terminal segment. Antibodies against the N-terminal region stain well in immunohistochemistry. By comparison, the labeling of embryonic Cajal-Retzius cells with antibodies directed against the C-terminal region is weaker, suggesting that this part of the molecule might be modified or not be as readily accessible in the tissue as the N-terminus.