Egr3‐dependent muscle stretch receptor morphogenesis and innervation homeostasis

Abstract

Muscle spindles are skeletal muscle receptors that mediate stretch reflexes and proprioception in vertebrates. Proprioception abnormalities are observed in many human neuropathies with unknown etiology and factors involved in sensory nerve‐stretch receptor homeostasis are poorly understood. During skeletal muscle development, sensory (Ia‐afferent) innervation is restricted to only a few myotubes which induces their transformation into intrafusal muscle fibers that form the stretch receptor core. The transcriptional regulator Egr3 is induced by sensory innervation and it has an essential role in stretch receptor morphogenesis, but whether its function is restricted to developing receptors and whether it has a role in innervation homeostasis is not known. Ablation of Egr3 using skeletal muscle specific knockout mice demonstrated its autonomous function in developing stretch receptors. Lineage tracing experiments using Egr3‐Cre knock‐in mice showed that stretch receptor differentiation is blocked in the absence of Egr3 and innervation fails to be maintained. Thus, Egr3 has an essential function in intrafusal muscle fiber differentiation and gene regulation required to maintain innervation homeostasis. (Support: NIH R01‐NS063078 and K26‐OD010945).