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Abstract
Loss of function mutations in GPR56, which encodes a G protein-coupled receptor, cause a specific human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). Studies from BFPP postmortem brain tissue and Gpr56 knockout mice have previously showed that GPR56 deletion leads to breaches in the pial basement membrane (BM) and neuronal ectopias during cerebral cortical development. Since α3β1 integrin also plays a role in pial BM assembly and maintenance, we evaluated whether it functions together with GPR56 in regulating the same developmental process. We reveal that loss of α3 integrin enhances the cortical phenotype associated with Gpr56 deletion, and that neuronal overmigration through a breached pial BM occurs earlier in double knockout than in Gpr56 single knockout mice. These observations provide compelling evidence of the synergism of GPR56 and α3β1 integrin in regulating the development of cerebral cortex.
Highlights
The interaction between cells and their environment is essential to brain development
We have previously showed that the pial basement membrane (BM) was properly formed in Gpr56 single knockout mouse embryonic brains before E12.5 (10 am on the 12th day of vaginal plugging), and regional pial BM breaches started to occur at E12.8 (6 pm on the 12th day of vaginal plugging) [14]
This study demonstrates synergistic activities of GPR56 and a3b1 integrin during cerebral cortical development
Summary
The interaction between cells and their environment is essential to brain development. Dystroglycan and intergrins are two major cell surface receptors that mediate cell-extracellular matrix (ECM) interactions [1,2,3,4]. Adhesion GPCRs are characterized by the presence of a large extracellular region and a G protein proteolytic site (GPS) domain that cleaves the receptor into N- and C-terminal fragments [7,8,9]. Mutations in one such adhesion GPCR, GPR56, cause a specific human brain malformation called bilateral frontoparietal polymicrogyria (BFPP) [10]. Histological analyses of postmortem human BFPP brain samples and Gpr knockout mice indicated that the histopathology of BFPP is a cobblestone-like brain malformation [14,15]
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