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Normal tissue morphogenesis relies on the proper coordination of cell division, differentiation, migration and adhesion. These cell developmental events involve a complex interplay between extracellular factors, cell surface receptors, the cytoskeleton and intracellular signaling networks.  Our major research interest focuses on understanding cerebral cortical development. Combined molecular genetics and cell biology approaches are used to unveil the molecular hierarchy that governs the structural complexity and evolutionary expansion of the cerebral cortex.

The cerebral cortex, as the largest part of the brain, consists of six highly organized layers of neurons, formed through overlapping steps of neural progenitor proliferation, neurogenesis, neural migration and differentiation. The precise control of each step of cortical development is essential for size, structure and function of the cerebral cortex.  Many genetic mutations have been found to disrupt one or multiple steps of corticogenesis and result in brain malformation and severe neurological syndromes.  Neurogenetic diseases under our current study include lissencephaly and periventricular heterotopia.  While lissencephaly manifest by a smooth cerebrum surface and disorganized neuronal layers, periventricular heterotopia is characterized by the misplacement of neuronal nodules along the brain ventricles.

Lissencephaly is often caused by heterozygous mutations of LIS1, which encodes an evolutionarily conserved cytoplasmic protein that physically and functionally interacts with Nde1 in regulating cerebral cortical neurogenesis and neuronal migration. We have demonstrated that the Lis1-Nde1 complex controls the self-renewal and differentiation of neural progenitor cells. Lis1-Nde1 double deficiency results in abnormal and excessive generation of cortical pioneer neurons at the expense of progenitors, leading to a striking reduction of the cerebral cortical size and the disorganization and inversion of cortical layers. By performing further genetic epistasis analyses in mice, current study in the lab is exploring genes that interact with Lis1-Nde1 in cerebral cortical development.

Periventricular heterotopia is predominantly an X-linked genetic disorder caused by mutations of FLNA, which encodes an actin binding protein. Our analyses with Flna knockout mice have suggested that Flna plays an essential role in the hemophilic cell-cell adhesion of radial glial neural progenitors and vascular endothelial cells. Ongoing analysis of Flna conditional knockout mice is aimed at understanding how altered cell adhesion of neural progenitors leads to the migration arrest of cortical neurons.

Genetic mutations of LIS1, NDE1 and FLNA not only cause severe malformations of the cerebral cortex, but also defects in the heart, blood vessels, bones, and hematopoietic cells. As cytoplasmic scaffolds, LIS1, Nde1 and FLNA interact with multiple proteins. They are not only required for the dynamic regulation of microtubule and actin cytoskeleton, but also play essential roles in cell signaling. With biochemical and cell biology approaches, current work in the lab also investigates protein-protein interactions of LIS1, Nde1 and FLNa in regulating neural progenitor cell morphology and mitosis; cell-cell and cell-extracellular matrix adhesion; cell migration and signaling transduction.