Mechanisms of structural plasticity in mature sensory axons: Role of BMP4 in female reproductive tract
University of Kansas
Molecular & Integrative Physiology
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Structural changes in sensory axons are associated with many peripheral nerve disorders. Degenerative loss or excessive sprouting of axons are hallmarks of sensory neuropathies or hyperinnervating pain syndromes respectively. While much is known about mechanisms of developmental axon growth or regenerative outgrowth following nerve injury, there is little information about mechanisms that can induce plasticity in intact adult axons. Lack of model systems, where extensive plasticity can be predictably induced under physiological conditions, has been a fundamental impediment in studying sensory neuroplasticity mechanisms in adult. The female reproductive tract presents a highly tractable model where sensory axons cyclically undergo extensive plasticity under the influence of estrogen. In rat, high estrogen levels induce reduction in vaginal sensory nerve density, and low estrogen conditions promote sprouting leading to hyperinnervation. We used this model to explore potential factors that can initiate spontaneous plasticity in intact sensory axons. We found that estrogen downregulates expression of Bone Morphogenetic Protein 4 (BMP4) in the vaginal submucosal smooth muscle cells which are associated with most innervation in the vagina. Thus under low estrogen conditions BMP4 expression increased in the smooth muscle, and the resulting trophic stimulus induced sprouting in associated nociceptive sensory axons. Activated Smad1 in nuclei of retrogradely labeled dorsal root ganglion neurons innervating the vagina confirmed BMP4 signaling under low estrogen conditions. When BMP4 was overexpressed in the vaginal submucosal smooth muscle by lentiviral transduction, elevated nerve density prevailed even under high blood estrogen levels. To identify the signaling mechanism by which BMP4 regulates sensory plasticity downstream from phospho-Smad1, we used the 50B11 sensory neuronal cell line. Receptor expression and outgrowth responses of the 50B11 cells to neurotrophins and growth factors resembled closely that of primary sensory neurons in culture, providing a reliable assay system. BMP4 treatment induced upregulation of Inhibitor of DNA binding 2 (Id2), a known downstream target of Smad1, in 50B11 cells; and Id2 overexpression induced increased neurite outgrowth. However, Id2 knockdown failed to abrogate BMP4-mediated increase of outgrowth in primary neurons, suggesting alternative mechanisms. We identified that BMP4 downregulates methyl CpG-binding protein 2 (MeCP2), a methylated-DNA binding protein and an epigenetic modifier and global transcriptional repressor, which is highly expressed in neurons. MeCP2 downregulation can prompt a global transcriptional upregulation inducing multiple genes, a situation characteristic of axonal growth initiation. Lentiviral knockdown of MeCP2 resulted in significant elevation of outgrowth in primary sensory neurons that matched growth induced by BMP4. Thus, we conclude that BMP4 is a factor capable of inducing plasticity in adult sensory axons. Smad1 activation by BMP4 induces sensory outgrowth by downregulating MeCP2 expression. These findings have significant impact on understanding of genetic and epigenetic mechanisms of adult peripheral neuroplasticity. It will also have strong implications in considering therapeutic measures in sensory neuroplasticity-associated disorders. The findings are particularly important in female pelvic pain syndromes like vulvodynia that are associated with excessive nerve sprouting under low estrogen conditions.
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