Neurotrimin is an estrogen-regulated determinant of peripheral sympathetic innervation.

Mechanisms underlying axon degeneration in peripheral neuropathies and during normal remodeling are poorly understood. Because estrogen induces widespread sympathetic axon degeneration in female reproductive tract smooth muscle, we surveyed estrogen-regulated genes in rat myometrium. Microarray analysis revealed that the neural cell adhesion protein neurotrimin (Ntm) was markedly up-regulated 6 hr and down-regulated 24 hr after injection of 17beta-estradiol, and real time RT-PCR confirmed this pattern of expression. Protein analysis by Western blotting showed that uterine Ntm protein is also up-regulated in vivo 6-24 hr following estrogen injection and that Ntm protein is increased selectively in the myometrium during the high-estrogen phase of the estrous cycle. Cultured myometrial smooth muscle cells display perinuclear accumulations of Ntm protein, and 17beta-estradiol also increases intracellular levels of Ntm and its secretion into the culture medium. To determine if neurotrimin is required for estrogen-induced sympathetic pruning, sympathetic neurons were cocultured with uterine smooth muscle cells transfected with siRNA directed against Ntm. Although estrogen inhibited neurite outgrowth in nontransfected cocultures, estrogen's ability to reduce sympathetic outgrowth was impaired substantially following Ntm down-regulation. This supports a role for neurotrimin in mediating estrogen-induced sympathetic pruning in some peripheral targets. Together with earlier studies, these findings support the idea that physiological sympathetic axon degeneration is a multifactorial process requiring dynamic regulation of multiple repellant proteins.