There are four major lines of ongoing research in the Piao lab. The first identifies cellular and molecular components of the GPR56 signaling pathways involved in cerebral cortical development. Our previous work has shown that first-born neurons, known as preplate neurons, express GPR56 most strongly in the frontal cortex, the region of the cortex most devastated in GPR56 mutations. Although the molecular mechanisms underlying the function of these preplate neurons remain largely unknown, our data indicates that GPR56 plays an important role in their function. In the next phase of research, we will continue to study how GPR56 mediates the interaction between preplate neurons and the pial basement membrane, particularly in an attempt to elucidate how it helps to define the boundary between the neocortex and pial basement membrane while providing a framework for the developing brain. At a molecular level, we discovered that collagen III is the ligand for GPR56 in the developing brain, whose binding activates the RhoA pathway by coupling to Gα12/13. Given that collagen III is a known constituent of the pial basement membrane, this strongly implies that GPR56-expressing migrating cells actively communicate with the basement membrane during normal brain development.
The second major line of ongoing research focuses on characterizing GPR56 and its binding partners in oligodendrocyte development and CNS myelination during development and remyelination. Oligodendrocytes are the main source of myelin in the CNS and myelinate by extending their processes and repeatedly wrapping them around the axons, allowing for more rapid signal transduction down the axons. Our research has previously shown that GPR56 plays an important role in the proliferation of oligodendrocyte precursor cells. We are currently working on identifying the ligands of GPR56 present during myelination, which are also expressed in other glial cells. Further, we are investigating the interactions between different glial cells mediated by GPR56 and their effects on CNS myelination/remyelination.
Microglia in Brain Development
Our third line of research is studying the role of microglial GPR56 in the development and function of the brain. Originating from the primitive myeloid cells in the yolk sac, microglia are tissue-resident macrophages in the CNS. First described in the late 1800s, microglia have long been considered innate immune cells that primarily serve to clear injured/dead cells and infectious agents from the CNS. However, increasing evidence suggest that microglial physiology is dominated by their physiological roles during neurodevelopment and pathological contributions to neurological disorders. GPR56 is highly expressed in the microglia of the postnatal brain with currently unknown function. Our work will shed light on the molecular mechanisms underlying microglia-mediated brain development.
The fourth major line of ongoing research is the identification of ligands for aGPCRs, the majority of which remain orphan receptors. These poorly studied GPCRs play a critically important role in brain development, synaptogenesis, myelination, blood brain barrier formation, and cancer progression. We have already found that collagen III is the ligand for GPR56 in the developing cerebral cortex, and, with our collaborators, we have discovered that Laminin-211 is a ligand for GPR126, which is crucial for peripheral nervous system myelination. Using in vitro biotinylation and proteomics approaches, we plan to continue to study aGPCRs. With the progressive discoveries of ligands, we plan to use this information in the future for drug-screening and development.