Neurotrophin-4 (NT-4) is the most recent member of the family of growth factors known as the neurotrophins. All neurotrophins (NGF, NT-3, BDNF and NT-4) are expressed by target tissues such as the skin during development. Expression begins at about E10.5, peaks at E14-15, and then steadily declines to low adult levels. Synthesis of neurotrophins by target tissues allows the survival of subsets of neurons and in so doing tailors the density and character of innervation. Previous studies have shown that overexpression of NGF in the developing epidermis of transgenic mice causes hyperinnervation of the skin and hypertrophy of the PNS (Albers et. al., 1994). Studies are proposed to determine if overexpression of NT-4 has similar capabilities. Transgenic mice will be isolated that express a gene construct in which the expression of the NT-4 gene is driven by the promoter and enhancer region of the epidermal keratin gene K14. Analysis of the K14-NT-4 transgenic mice will include: 1) neuronal cell counts in the trigeminal and nodose ganglia of control and transgenic mice, 2) Chemical characterization of neurons (using immunocytochemistry and in situ hybridization) to determine whether alteration in transmitter, peptide, or trk receptor phenotype occur, and 3) characterization of the peripheral innervation density and character. These studies represent one of the first to evaluate the in vivo function of NT-4 on the development and function of the PNS and will provide essential data on its applicability as a therapeutic agent.
