Schwann cells (SCs) are the myelinating glia of the peripheral nervous system (PNS) that associate with and wrap around axons to form the insulating myelin sheath. During development, immature SCs select appropriately sized axons (a process termed radial sorting) and repeatedly wrap their membranes around their selected axon. The importance of SC myelin is best underscored in diseases in which SC dysfunction leads to peripheral neuropathies (e.g., Charcot-Marie-Tooth Disease). Advances in identifying growth factors and signaling molecules expressed by SCs reveal the myriad roles of glial cells in the nervous system and their interactions with each other, with neurons, and with the surrounding extracellular matrix (ECM). We have previously identified the adhesion G protein-coupled receptor (aGPCR) GPR56/ADGRG1 as a critical regulator of PNS development. Loss of Gpr56 function in zebrafish and mouse mutants results in both early developmental and later maintenance phenotypes in the PNS. In spite of these key functions, however, it is unclear what developmental cues activate GPR56 in SCs.
Aim 1 will determine the binding partners that regulate Gpr56 activity during development. In other contexts, GPR56 has two known binding partners, the ECM proteins collagen III and tissue transglutaminase 2. Interestingly, however, an unbiased proteomics screen has identified additional candidate binding partners for GPR56 in the PNS. We have generated new zebrafish mutants in these genes by CRISPR/Cas9-mediated genome editing, and I will perform biochemical, ultrastructural, and signaling analyses to determine the requirement of these candidates in Gpr56 activity.
Aim 2 will define the roles of Gpr56 in adult peripheral nerve. I will determine if Gpr56 is required for myelin maintenance, repair, and remyelination after nerve injury using inducible mouse models. Together, my studies can define mechanisms by which Gpr56 controls PNS development and repair and may suggest roads towards new therapies for human neuropathies, myelin diseases, and nerve injury.
Myelination is critical specialization in the vertebrate nervous system, resulting in a fatty, multilayered ensheathment of axons. Defects in myelin can cause peripheral neuropathies, but despite the prevalence and severity of these diseases, no effective therapeutics exist. Here, we propose to determine how a G protein- coupled receptor Gpr56 regulates myelination, maintenance, and repair after injury; these studies are highly relevant to public health as they will provide a better understanding of the molecular control of peripheral myelination and remyelination.
| Ackerman, Sarah D; Luo, Rong; Poitelon, Yannick et al. (2018) GPR56/ADGRG1 regulates development and maintenance of peripheral myelin. J Exp Med 215:941-961 |
| D'Rozario, M; Monk, K R; Petersen, S C (2017) Analysis of myelinated axon formation in zebrafish. Methods Cell Biol 138:383-414 |
| Mogha, Amit; D'Rozario, Mitchell; Monk, Kelly R (2016) G Protein-Coupled Receptors in Myelinating Glia. Trends Pharmacol Sci 37:977-987 |
