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Defective neurogenesis in citron kinase knockout mice by altered cytokinesis and massive apoptosis.
Citron-kinase (Citron-K) has been proposed by in vitro studies as a crucial effector of Rho in regulation of cytokinesis. To further investigate in vivo its biologic functions, we have inactivated Citron-K gene in mice by homologous recombination. Citron-K-/- mice grow at slower rates, are severely ataxic, and die before adulthood as a consequence of fatal seizures. Their brains display defective neurogenesis, with depletion of specific neuronal populations. These abnormalities arise during development of the central nervous system due to altered cytokinesis and massive apoptosis. Our results indicate that Citron-K is essential for cytokinesis in vivo but only in specific neuronal precursors. Moreover, they suggest a novel molecular mechanism for a subset of human malformative syndromes of the CNS.
Animals, Apoptosis/genetics, Ataxia/etiology, Brain/embryology, Brain/pathology, Cell Division/genetics, Cyclin D1/metabolism, DNA/biosynthesis, Intracellular Signaling Peptides and Proteins, Mice, Mice, Knockout, Neurodegenerative Diseases/complications, Neurodegenerative Diseases/genetics, Neurons/metabolism, Neurons/pathology, Polyploidy, Protein-Serine-Threonine Kinases/biosynthesis, Protein-Serine-Threonine Kinases/deficiency, Seizures/etiology, Stem Cells/metabolism, Stem Cells/pathology, rho-Associated Kinases
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