DEVELOPMENT OF MECHANORECEPTORS--ROLE OF NEUROTROPHINS

Medical College Of Wisconsin, Milwaukee WI

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Abstract

Merkel cells are slowly adapting sensory receptors in the skin that are innervated by Abeta sensory neurons. Virtually nothing is known about the cellular and molecular mechanisms that control development and innervation of Merkel cells. My advisor, Prof. Grim, and his collaborators have shown that Merkel cells are derived from the neural crest and that their precursors migrate in the ventrolateral migratory pathway in the subectodermal space. The proposed work is designed to elucidate some of the roles growth factors play in the development of quail neural crest cells into Merkel cells. In Aim 1, Merkel cells in culture will be characterized at the ultrastructural level and compared to Merkel cells in the intact organism. In Aim 2, the expression during embryonic development of pertinent growth factor receptors by Merkel cell precursors and maturing Merkel cells will be elucidated by indirect immunohistochemistry and in situ hybridization. Additionally, the autocrine and/or paracrine expression of the receptor ligands will be determined. Candidate growth factors include stem cell factor (SCF), epidermal growth factor (EGF), nerve growth factor (NGF) and neurotrophin-3 (NT-3). By use of the neural crest cell colony assay that has been developed in Prof. Sieber-Blum's laboratory, I propose in Aim 3 to assess the role of pertinent growth factors (as determined in Aim 2) in the survival, proliferation and differentiation of Merkel cells. The proposed work has relevance to human neurological disease. In individuals with anhidrotic ectodermal dysplasia, and in the corresponding mouse model, Tabby, there are no Merkel cells (Srivastava et al., 1997; Vielkind et al., 1995). This is most likely due to down-regulation of the EGF receptor. In vitiligo, Merkel cells as well as melanocytes are lost (Kumar Bose, 1994). A disrupted neurotrophin-3 gene in mice causes perinatal loss of Merkel cells and other neurodegenerative symptoms (Airaksinen et al., 1996). Merkel cell carcinoma (small, intermediate and trabecular types) is a relatively frequent tumor (Schmidt et al., 1998). Insights into the mechanisms that regulate normal Merkel cell development may prove useful in future approaches for the prevention or treatment of neurological disease.