Developmental genetic malformations of the cerebral cortex underlie a large fraction of clinical cases of epilepsy and mental retardation. A powerful tool for understanding these developmental disorders is to analyze their causative genes. Heterozygous mutations of the LIS1 gene are known to cause lissencephaly (smooth brain), a severe neurogenetic syndrome manifested by intractable epilepsy, profound mental retardation and early infantile death. LIS1 gene encodes a cytoplasmic protein with no apparent intrinsic enzymatic activity;its molecular and cellular function may act via protein-protein interactions. We show that LIS1 interacts with Nde1 both physically and functionally. By analyzing an allelic series of Lis1-Nde1 double mutant mice, we demonstrated that Lis1 and Nde1 form a dosage dependent complex in regulating the self-renewal and differentiation of neural progenitors. Lis1-Nde1 double loss of functional mutations resulted in severe mitotic, morphological and adhesion defects of neural progenitors at the onset of cerebral cortical neurogenesis, leading to an over 80% reduction in the size of the cerebral cortex and severe disorganizations of cortical neurons. We propose to perform detailed analyses on cortical developmental defects of Lis1 and Nde1 mutant mice in Specific Aim 1 to understand how the proliferative self-renewal and the neurogenic differentiation of neural progenitors are controlled by their basic structural features such as morphology, mitotic pattern, lateral adhesions and cytoarchitectural organizations. We will also explore the cell molecular mechanisms that underlie the neurogenesis control by the Lis1-Nde1 complex in Specific Aim 2 through studying Lis1- Nde1 mutant progenitors in cultures and analyzing Nde1 binding proteins. The proposed work will help to understand the molecular control of cortical neurogenesis by the Lis1- Nde1 pathway, and will also gain a broader insight into mechanisms governing cerebral cortex development as well as pathogenesis of lissencephaly and other genetic cortical malformation diseases.
Mutations of the LIS1 gene cause lissencephaly syndrome (smooth brain), a severe developmental genetic disorder with a malformed cerebral cortex, intractable epilepsy and profound mental retardation. The proposal outlines combined mouse genetic and cell biological experiments to study the function of LIS1 and its associated Nde1 genes in regulating the self- renewal and neurogenesis during cerebral cortical development.
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