We are interested in the role of adhesion GPCRs in brain development and malformation. Genetic studies have identified mutations in a specific adhesion GPCR, GPR56, which is the underlying cause of a severe human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). Our subsequent studies revealed that GPR56 interacts with its ligand, collagen III, in the developing brain to regulate the integrity of the pial basement membrane and the proper positioning of the migrating neurons.
In parallel, we are examining how GPR56 signaling regulates myelination. Brain MRIs of patients with BFPP reveal associated myelination defects in the region of periventricular white matter. Oligodendrocytes are largely responsible for the development of myelin in those areas. It is possible that GPR56 signaling affects the interaction of oligodendrocytes and the axons, thus regulating myelination in the central nervous system.
We are also investigating the functional domains of the GPR56 molecule, the ligand(s) that activate GPR56, and the signal transduction events that are triggered by GPR56 activation. Ultimately, we hope that our work will delineate novel signaling pathways that control the development of the mammalian brain and shed light on the intrinsic causes of brain malformations.