Title:
A unique role of motor proteins and their friends in corticogenesis:
landscape of cytoplasmic dynein and nud family proteins.
Shinji Hirotsune
Osaka City University Graduate School of Medicine
Department of Genetic Disease Research
Abstract:
Cortical formation in the developing brain is a highly complicated process involving neuronal production (through symmetric or asymmetric cell division) interaction of radial glia with neuronal migration, and multiple modes of neuronal migration. In particular, neuronal migration is an essential step to give rise to normal cortex that consists from the six layers laminated structure. To address underlying molecular mechanism, human developmental disorders or mouse mutants displaying defective neuronal migration provide a unique avenue.
Lissencephaly is one of representative human developmental disorders, which is characterized by smooth cerebral surface and thick cortex. Lissencephaly are an important cause of mental retardation and severe epilepsy in humans, and many of the genes responsible for these conditions have been identified, including LIS1 and DCX . Heterozygous deletions or mutations of LIS1 are the most common cause of lissencephaly in humans. We previously reported that LIS1 is part of a complex that includes NDEL1 and 14-3-3 epsilon that is essential for the regulation and localization of cytoplasmic dynein (light and heavy chains) to regulate centrosomal protein localization and function as well as microtubule dynamics. In addition, we uncovered that mNUDC, mammalian homologue of NudC is essential for puls-end directed transport of cytoplasmic dynein. In the series of these experiments, we found that LIS1 is degraded by calpain, calcium dependent cysteine protease. Intriguingly, calpain inhibitors prevent degradation of LIS1, which provided beneficial effects in Lis1 mutated mice.
Currently, we are investigating a structural feature of dynein-LIS1-microtubule complex, and an activating mechanism of idling dynein. Our work will provide essential insights for understanding molecular mechanism of neuronal migration and regulation of intracellular transport by motor proteins.
References:
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