The union of sperm and egg at fertilization is an essential step in reproduction. In mammals, including human, sperm must first bind to the egg zona pellucida and complete the acrosome reaction before fusing with the egg. The zona pellucida initiates acrosome reactions by driving calcium entry into sperm through TRPC channels. However, the mechanisms by which the zona pellucida regulates the conductance through these sperm ion channels are poorly understood and represent a major gap in our knowledge. Based on preliminary and published data, a working hypothesis is developed that the zona pellucida drives the synthesis of phosphatidylinositol-4, 5-bisphosphate (PIP2) and that this lipid regulates the function of two members of the TRPC channel family by two distinct mechanisms.
The aims of this proposal are to: 1) determine the mechanism by which the zona pellucida regulates PIP2 synthesis and metabolism;2) determine the mechanisms by which that PIP2 controls calcium conductance through TRPC channels;and 3) determine how sperm capacitation and seminal plasma components contribute to TRPC channel function and to fertilization. These studies are relevant in two regards. First, they may advance our understanding of the basic biology of fertilization. Second, there may be therapeutic consequences of these studies both with regard to the treatment of human infertility and for the design of novel contraceptives. In particular, the effects of PIP2 metabolites that are produced in sperm in response to zona pellucida stimulation are directly relevant to the control of the human acrosome reaction.
This project focuses on the control of the sperm acrosome reaction by the zona pellucida. The acrosome reaction is an obligatory early event in the fertilization process and insights into the underlying mechanisms may lead to strategies to control soaring population, which now exceeds 6,700 million world-wide, as well as provide novel treatments of infertility, which is estimated to affect 10-15% of couples in the US. The strategy proposed here is to identify the molecular mechanisms by which eggs activate sperm during fertilization in the mouse, where material is readily available. This sets the stage for examination of those pathways in human.
|Jungnickel, Melissa K; Sutton, Keith A; Baker, Mark A et al. (2018) The flagellar protein Enkurin is required for mouse sperm motility and for transport through the female reproductive tract. Biol Reprod 99:789-797|
|Sigg, Monika Abedin; Menchen, Tabea; Lee, Chanjae et al. (2017) Evolutionary Proteomics Uncovers Ancient Associations of Cilia with Signaling Pathways. Dev Cell 43:744-762.e11|
|Sutton, Keith A; Jungnickel, Melissa K; Florman, Harvey M (2008) A polycystin-1 controls postcopulatory reproductive selection in mice. Proc Natl Acad Sci U S A 105:8661-6|
|Jungnickel, Melissa K; Sutton, Keith A; Wang, Yanli et al. (2007) Phosphoinositide-dependent pathways in mouse sperm are regulated by egg ZP3 and drive the acrosome reaction. Dev Biol 304:116-26|
|Sutton, Keith A; Jungnickel, Melissa K; Ward, Christopher J et al. (2006) Functional characterization of PKDREJ, a male germ cell-restricted polycystin. J Cell Physiol 209:493-500|
|Sutton, Keith A; Jungnickel, Melissa K; Wang, Yanli et al. (2004) Enkurin is a novel calmodulin and TRPC channel binding protein in sperm. Dev Biol 274:426-35|