Etv5 Is Required for Peripheral Nerve Function and the Injury Response

The development of Schwann cells, which myelinate axons in the peripheral nervous system, is critically dependent on MEK/ERK signaling. While Ets-domain transcription factors (Etv1, Etv4, Etv5) are downstream effectors of this pathway, only Etv1 has been specifically linked to Schwann cell development. Here, we examined the functions of Etv5, which is expressed in Schwann cell precursors, neural crest cells and satellite glia, at embryonic stages and at low levels in mature Schwann cells. In hypomorphic Etv5^tm1Kmm homozygous mutant mice, no overt defects in Schwann cell differentiation were observed at embryonic stages. To study the function of Etv5 in juvenile (postnatal days 21-30) and mature adult (6 month) mice, we generated Etv5 conditional knock-outs (cKOs) using a Sox10-Cre driver. In juvenile male Etv5-cKO mice, Schwann cell numbers increased normally after a peripheral nerve crush injury, a response that was attenuated by 6 months. Transmission electron microscopy of the naive sciatic nerve revealed a decline in axonal diameter and perturbed myelination in Etv5-cKO male and female mice. The innervated gastrocnemius muscle declined in area and volume in Etv5-cKO mice of both sexes, suggesting nerve structural abnormalities cause muscle atrophy. However, control and Etv5-cKO male and female mice performed similarly in motor behavior tests after a crush injury. Thus, Etv5 is not essential for Schwann cell differentiation, but Etv5 plays a crucial role in the age-dependent regulation of Schwann cell function, including nerve repair and the maintenance of axonal integrity in mature peripheral nerves.