GPR56 and the Developing Cerebral Cortex: Cells, Matrix, and Neuronal Migration

GPR56, a member of the adhesion G protein-coupled receptor (GPCR) family, is integral to the development of the cortex, as mutations in GPR56 cause bilateral frontoparietal polymicrogyria (BFPP). BFPP is a cobblestone-like cortical malformation, characterized by overmigrating neurons and the formation of neuronal ectopias on the surface of the brain. Since its original cloning a decade ago, GPR56 has emerged from an orphaned and uncharacterized protein to an increasingly well-understood receptor, both in terms of its signaling and function. Collagen III is the ligand of GPR56 in the developing brain. Upon binding to collagen III, GPR56 activates RhoA via coupling to Gα_12/13. This pathway appears to be particularly critical in the preplate neurons, which are the earliest born neurons in the cortex, as the expression pattern of GPR56 in these neurons mimics the anterior to posterior gradient of malformation associated with loss of GPR56 in both humans and mice. Further characterizing the role of GPR56 in the preplate will shed light on the mechanism of cortical development and patterning.