Regulation of Cortical Development by GPR56 Signaling

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DESCRIPTION (provided by applicant): Mutations of regulatory genes in the developing central nervous system are frequently associated with human neurological diseases. Disorders in neuronal cell proliferation, migration, and lamination, in particular, lead to mental retardation and epilepsy. Our long-term goal is to study the molecular mechanisms that underlie cortical development and their related neurological disorders. Using positional cloning, we recently demonstrated that loss-of-function mutation in GPR56, an orphan G protein-coupled receptor (GPCR), causes a specific cortical malformation known as bilateral frontoparietal polymicrogyria (BFPP). Identification of GPR56 as a causative gene of BFPP leads to the specific hypothesis of this application that the signaling pathway of GPR56 is crucial in regulating cortical development. Our hypothesis is based on published and preliminary observations that: (1) mutations in GPR56 cause a specific human cortical malformation, BFPP; (2) mouse Gpr56 mRNA is expressed mainly in neuronal progenitor cells, suggesting that it may play an important role in cortical development and patterning; and (3) Gpr56 knockout causes cortical dysplasia in mice; (4) GPR56 functions synergistically with 13 integrin and Gpr56/13 integrin double knockout mice have more severe and extensive cortical dysplasia. Based on these observations, the experimental focus of this proposal is on the functional analysis of GPR56 in mouse models. The specific aims are to: (1) delineate the pathogenesis of BFPP; (2) investigate the potential interaction of GPR56 and 13 integrin; and (3) study GPR56 protein trafficking. Abnormal brain development frequently causes human neurological disorders such as mental retardation and seizures. The gene GPR56 is important in brain development, and its mutation causes brain malformations in humans. The proposed research is designed to study GPR56-mediated brain development and its related pathophysiology.