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The research in the Piao lab is directed at understanding how cells communicate with their extracellular matrix during normal brain development as well as in the case of neurological diseases. In particular, we are investigating signaling mechanisms employed by a member of the adhesion G protein-coupled receptor family, GPR56. While characterizing a newly defined human brain malformation, we discovered that GPR56 is the disease-causing gene. When GPR56 is mutated, the formation of the cerebral cortex is severely disrupted, particularly in the frontal cortex.

Collagen III containing pial basement membrane directly contact to GPR56 expressing cells in the mouse developing brain. Left: Double IHC of collagen III/GPR56 on E11.5 wild-type mouse brains showing that GPR56 expressing cells (green) directly contact with basement membrane containing collagen III (red). Right: Immunogold-positive collagen III (arrowheads) is expressed in the pial basement membrane. Both migrating neuron (MN) and radial glial endfeet (EF) have direct contact to the collagen III-containing pial basement membrane.

There are two major lines of ongoing research in the lab. The first is to identify molecular components of GPR56 signaling pathways and the mechanisms by which GPR56 pathways are activated and governed during brain development and malformation. To this end, we discovered that collagen III is the ligand of GPR56 in the developing brain and that the binding of collagen III to GPR56 activates RhoA pathway by coupling to Gα12/13.This finding was particularly interesting, as collagen III is a constituent of the extracellular matrix that covers the cortex, known as the pial basement membrane. The fact that the ligand of GPR56 was in the pial basement membrane provided strong evidence that GPR56-expressing migrating cells must be actively communicating with the basement membrane in order to ensure proper brain development.

GPR56 expression is gradually decreased from anterior to posterior in Tuj1-positive postmitotic neurons. Double IHC of Tuj1 (red) and GPR56 (green) was performed on sagittal sections of E10.5. GPR56 expression is highly correlated with Tuj1-positive postmitotic neurons in the anterior region at E10.5, but not in the posterior region.

The second major line of ongoing research is to determine which cells are chiefly responsible for this interaction. We found that the first-born neurons, known as preplate neurons, expressed GPR56 most strongly in the frontal cortex – the same region of the cortex that is most devastated when GPR56 is mutated. 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 our research, we will continue to study how GPR56 mediates the interaction between the preplate neurons and pial basement membrane, particularly in an attempt to elucidate how they work together to define the boundary between the neocortex and the pial basement membrane while providing a framework for the developing brain.

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