The role of APC in primary cilia functions during cortical progenitor development

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Abstract

? DESCRIPTION (provided by applicant): Construction of the cerebral cortex is dependent on specialized cortical progenitors called Radial Glial Cells (RGCs). These cells function both as a source of neurons and an instructive scaffold for neuronal migration and placement. Disrupted formation, polarity, and differentiation of RGCs lead to aberrant placement and connectivity of neurons in the human cerebral cortex, an underlying cause of a spectrum of neurodevelopmental disorders including epilepsy, pediatric brain tumors, schizophrenia, and autism. Thus, a critical question to be answered is what are the essential molecular mechanisms underlying RGC development and function during corticogeneisis. Our lab previously showed that RGC polarity and function is dependent on Adenomatous Polyposis Coli (APC), a multifunctional adaptor protein. Further, APC deletion disrupts primary cilia function and maintenance in RGCs. Primary cilia signaling in RGCs is essential for RGC development. In humans, mutations in APC leads to autism spectrum disorders as well as brain tumor polyposis. Here, we propose to test the hypothesis that APC activity in primary cilia functions to integrate ciliary signaling mechanisms essential for the development and differentiation of RGCs during the construction of the cerebral cortex. Towards this goal, we will (1) define the localization of APC in distinct domains of RGC primary cilia, (2) examine how conditional loss of APC in cortical progenitors affects cilia structure, localization, and activity, and (3) investigat how primary cilia signaling defects caused by APC deletion alters radial progenitor development and differentiation. Collectively, this work will define the integrative role of APC in primary cilary signaling necessary for the appropriate development of cortical progenitors. Furthermore, deciphering of the cilia-related molecular cascades and neurodevelopmental pathways, whose disruptions are integrally related to brain malformations and neurobehavioral abnormalities in humans, will contribute towards devising optimal therapeutic strategies for these brain disorders.