My lab investigates molecular and cellular mechanisms that regulate spermatogenesis, sperm motility and fertilization. Our studies use the male reproductive system as a model to investigate fundamental processes that control cell proliferation and differentiation. In terms of human health, the long-term goal of these studies is to provide new insights for the development of contraceptives, the clinical management of infertility, and the assessment of reproductive toxicants in the male.

A major focus of our current research is sperm energy metabolism, particularly the function of glycolytic isozymes with restricted expression in the male germline. Our gene targeting studies of two germ cell-specific isozymes provide compelling evidence that glycolysis is essential for sperm motility and male fertility in the mouse. Males lacking either glyceraldehyde 3-phosphate dehydrogenase-S (GAPDHS) or phosphoglycerate kinase 2 produce sperm with severe motility defects and very low ATP levels. GAPDHS has a unique N-terminus that is required for targeting this isozyme to the fibrous sheath, a cytoskeletal structure in the sperm flagellum that defines the limits of the principal piece. We recently identified three new aldolase isoforms in mouse sperm, including two isoforms with novel N-terminal extensions that are tightly bound to the fibrous sheath. Distinctive features of the germ cell-specific glycolytic enzymes may be important for compartmentalization of glycolysis in the principal piece and/or altered activity of this key metabolic pathway.

We are using homology modeling, X-ray crystallography, and in silico docking studies to determine if the germ cell-specific glycolytic enzymes have distinct enzymatic properties. Two compounds identified in these analyses selectively inhibit GAPDHS. These studies underscore the utility of structure-based drug design and support the concept that sperm-specific glycolytic enzymes may be excellent contraceptive targets.

We investigate several proteins with restricted expression during spermatogenesis, with the goal of identifying key regulators of this developmental process. One current focus is speriolin, a unique protein that associates with activators of the anaphase promoting complex. Expressed only in the late meiotic and post-meiotic stages of spermatogenesis, speriolin is localized in the centrosome and is present in the connecting piece of the sperm flagellum. Our gene targeting studies indicate that speriolin has important functions in spermatogenesis, sperm structure and male fertility.