The Transcription Factor Egr3 Modulates Sensory Axon–Myotube Interactions during Muscle Spindle Morphogenesis

Abstract

The Egr family of zinc-finger transcription factors, consisting of Egr1, Egr2, Egr3, and Egr4, are involved in cellular growth and differentiation. Adult Egr3-deficient mice are ataxic and lack muscle spindle proprioceptors that normally develop at the sites of Ia afferent-myotube contacts during embryogenesis. To resolve whether spindles form and then degenerate, or whether they never form in the absence of Egr3, we examined the spatiotemporal expression of Egr3 relative to spindle development. In wild type mice, Egr3 was expressed in developing myotubes shortly after they were innervated by Ia afferents and its expression was controlled by innervation because it dissipated following nerve transection. In Egr3-deficient mice, myotubes received Ia afferent innervation and assembled normally into spindles during embryogenesis. However, newborn Egr3-deficient spindles had few internal myonuclei in intrafusal fibers and thin capsules. Moreover, slow-developmental myosin heavy chain was not induced in embryonic Egr3-deficient spindles suggesting that impairments in differentiation were present before they could be detected morphologically. After birth, sensory and motor innervation withdrew from the Egr3-deficient spindles, and the spindles disassembled. In spite of the spindle disassembly and retraction of afferents from muscles, the cell bodies of proprioceptive neurons within dorsal root ganglia were retained. We conclude that Egr3 has an essential role in regulating genes required for the transformation of undifferentiated myotubes into intrafusal fibers, and hence for the phenotypic differentiation of spindles.