The proposed research is designed to develop a better understanding of the mechanisms that control and maintain testis development and function. Of particular interest are the cell-cell interactions that regulate testis growth, size, and morphogenesis which directly influence male fertility and sperm production. Preliminary research has demonstrated that two families of paracrine growth factors directly influence testis development and function. The general hypothesis examined is that locally produced paracrine growth factors are essential for cell growth and differentiation during embryonic and postnatal testis development and that this directly influences male fertility and sperm production in the adult. Abnormal testis development and male infertility may in part be due to inappropriate control of testicular cell growth and differentiation during development. The specific hypothesis tested is that subsequent to genetic male sex determination (e.g. sry) precursor Sertoli cells produce neurotropins (e.g. nt3) that act as a chemotactic agent for specialized cells in the mesonephros to migrate into the developing testis and develop into precursor peritubular cells that produce growth factors (e.g. hepatocyte growth factor) to promote seminiferous cord formation from aggregates of Sertoli and primordial germ cells, and that following this morphological testis differentiation (i.e. cord formation) that transforming growth factors (i.e. TGFb) are induced by similar locally produced growth factors to regulate the rapid cell growth and cell survival associated with embryonic testis development. Preliminary studies indicate that the transforming growth factor family is critical for embryonic testis growth. Preliminary studies also indicate that the neurotropin family of factors (e.g., NT3) has a critical role in the morphogenesis of testis development (i.e., sex cord or seminiferous tubule formation). Both growth factor families have been demonstrated to influence germ cell development and survival. This non-neuronal action of the neurotropins when blocked inhibited normal testis development and morphogenesis. Further analysis of these phenomena and the experimental approach consists of the following specific aims: 1. investigate the role of the neurotropin growth factor family in testis development, 2. investigate the role of the transforming growth factor- beta family in testis development. 3. investigate the physiological function of these growth factors during testis development on male fertility. The completion of these studies will provide insight into the cell-cell interactions and factors that control embryonic testis growth and function. Testicular cell (e.g., Sertoli) growth and differentiation is essential for embryonic, prepubertal, pubertal, and adult testis function. Abnormal control of these cell-cell interactions is anticipated to result in male infertility. Inappropriate expression of the growth factors or receptors may result in subfertile males. Addition of these factors may enhance and improve male fertility. Therefore, observations from the current proposal will provide a better understanding of normal and abnormal testis development and function. It is anticipated that the observations will lead to the design of future: therapeutic treatments for male infertility.
| Memon, Mushtaq A; Anway, Matthew D; Covert, Trevor R et al. (2008) Transforming growth factor beta (TGFbeta1, TGFbeta2 and TGFbeta3) null-mutant phenotypes in embryonic gonadal development. Mol Cell Endocrinol 294:70-80 |
