William H. Walker, PhD

The research in the Walker lab is focused on how hormone signals in the testis maintain male fertility.  Specifically, we are interested in the molecular mechanisms by which hormones such as follicle-stimulating hormone and testosterone support the survival and development of germ cells as they mature into sperm.  The lab is working towards identifying hormone targets in testis cells that are required to maintain fertility. The results of these studies will identify previously unknown causes of male infertility, deliver targets for male contraceptive drug development and provide alternatives for surgical neutering of companion animals.

Testosterone signals required for male fertility

Testosterone is essential for the production of sperm and male fertility. Previously, testosterone was thought to act through the androgen receptor to only regulate gene expression in Sertoli cells that support sperm development (the classical testosterone signaling pathway). The Walker lab discovered an alternative pathway of testosterone action (the non-classical pathway) that causes androgen receptor to activate kinase enzymes in Sertoli cells that required to support the production of sperm. The Walker lab is now investigating the mechanisms by which the non-classical pathway supports male fertility. Transgenic mice were created that produce androgen receptors that can only activate the classical testosterone signaling pathway or only the non-classical pathway. Studies are underway to identify the cellular factors and processes that are regulated by each testosterone pathway. These studies will provide long-needed answers to the question of how testosterone supports spermatogenesis and provide targets for infertility therapies. The Walker lab is also studying inhibitors that specifically block individual testosterone pathways as novel strategies for male contraception.

The SHP2 phosphatase is required to maintain germ line stem cells

The continuous production of sperm through a man’s lifetime requires the constant replenishment of developing germ cells by germ line stem cells (spermatogonial stem cells).  To maintain sperm production, the spermatogonial stem cells must balance the need to maintain a pool of stem cells with the production of cells committed to differentiate into sperm.  The Walker lab found that stem cell proliferation in the testis ceased and the stem cells died in transgenic mice after the elimination of the SHP2 tyrosine phosphatase encoded by the Ptpn11 gene. Thus, in the absence of SHP2, germ cells cannot be replenished and sperm are not produced. Additional studies determined that SHP2 also was required in Sertoli cells for germ cell attachment and to maintain the blood testis barrier that are essential for fertility. The delivery of chemical inhibitors of SHP2 to the testis resulted in the permanent elimination of stem cells, developing germ cells and sperm.  The Walker lab is working to refine the targeted delivery of SHP2 inhibitors to the testis so they may act as more humane alternatives to surgical neutering of male companion animals and as a solution to the overpopulation of feral animals.