Xianhua Piao

Our research focuses on molecular mechanisms that control both normal brain development and brain malformations. Starting with knowledge of a gene implicated in brain malformation in humans, we are using mouse models to unravel signaling pathways that specify the cellular architecture of the cortex. G-protein coupled receptors (GPCRs) are cell membrane proteins that orchestrate intracellular responses to external cues. We are particularly interested in a unique subfamily of GPCRs called adhesion GPCRs. Genetic studies have identified mutations in a specific adhesion GPCR, GPR56, that underlie bilateral frontoparietal polymicrogyria (BFPP)--a malformation named after the appearance of an excessive number of small folds, or gyri, on the surface of the brain (for details, see this PDF). On MRIs of patients with this condition, the cortex often appears to be comprised of an excessive number of small gyri, resulting in a scalloped appearance of the grey-white matter junction. Click to see pictures of BFPP in the human brain and learn more about GPR56. To investigate the specific tissue abnormalities underlying this disorder, we are characterizing the brains of mice lacking GPR56. We find that loss of GPR56 results in a "cobblestone-like" cortex--ectopic neuronal outgrowths on the brain surface cause it to resemble cobblestones. Studies in the cortex and cerebellum reveal that those neuronal ectopias are accompanied by disruption of the pial basement membrane, a thin layer of tissue ensheathing the surface of the brain. 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 and thus regulates myelination in the central nervous system. Using biochemical approaches, 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 underlying causes of brain malformations.