Grants We Funded

Abstract
Peripheral nerve injuries can be devastating. Clinical management of peripheral nerve injuries is limited temporally, resulting in permanent paralysis or functional limitation. The molecular mechanisms responsible for this limitation are not known. Many investigations have focused on neuroregeneration or on myelinating Schwann cells located along the nerve axon, but additional understudied components of the nerve-synapse-muscle relationship may hold functional significance.
The peripheral nervous system (PNS) is supported by two main categories of glial cells: myelinating and non-myelinating Schwann cells. Non-myelinating Schwann cells in the PNS include Remak cells along the axon and terminal Schwann cells at the synapse. Non-myelinating Schwann cells display functional plasticity providing guidance, trophic support, and regenerative assistance to neurons and may provide critical opportunities for therapeutic benefit. Investigation of the non-myelinating lineage, however, has been limited by few specific molecular makers and tools for study.
An orphan G protein-coupled receptor, Gpr126, is essential for myelinating Schwann cell development. Gpr126 mutant mice display abnormalities not only in the myelinating lineage, but also in Remak Schwann cells, motor nerve, and muscle morphology. We hypothesize that Gpr126 is essential for terminal Schwann cell development, but this has not been investigated. As a G protein-coupled receptor, Gpr126 represents an excellent therapeutic target for stimulating repair in patients with peripheral nerve injury. The goal of this study is to define the function of Gpr126 in terminal Schwann cell development at the neuromuscular junction.
In this study, we focus on evaluating the roles of terminal Schwann cells in development and reinnervation. In the first aim, we will define the terminal Schwann cell phenotype in Gpr126 mutant mice with immunostaining and electron and confocal microscopy at different developmental time points. In the second aim, we will test the hypothesis that terminal Schwann cells are necessary for muscle reinnervation following injury in both cranial and peripheral nerve models via laser ablation of these cells. Together, these studies will provide important initial data on terminal Schwann cell development, function, and molecular signaling, which could potentially provide important clinical therapeutic interventions following nerve injury. Modification of terminal Schwann cell function and signaling may provide a key to prolonging the critical window during which muscle reinnervation can occur or protecting injured muscle from degenerative effects following denervation.

Biography
Dr. Alison Snyder-Warwick is an Associate Professor of Surgery in the Division of Plastic and Reconstructive Surgery and Director of the Facial Nerve Institute at Washington University in St. Louis. Dr. Snyder-Warwick completed medical school, a research fellowship in Developmental Biology, and surgical residency training all at Wash U. She then travelled to Toronto, Canada for specialized training in pediatric plastic surgery and pediatric microsurgery at the Hospital for Sick Children. Dr. Snyder-Warwick’s main clinical focus includes pediatric plastic surgery and reconstruction for facial nerve disorders, treatment of facial clefts, reconstruction of brachial plexus birth injuries, gender-affirming surgery, and pediatric and adult microsurgical procedures. Her clinical interests have led to pioneering basic science research investigations involving the terminal Schwann cell, a unique glial cell present at the nerve-muscle interface. Dr. Snyder-Warwick is passionate about helping children and adults with facial paralysis, nerve-related injuries, and facial anomalies and is committed to studying novel techniques of optimizing care for people affected by peripheral nerve pathology and facial differences.