Sunday, May 11, 2025
5/11/2025
CatSper regulation of sperm physiology and fertility - PROJECT SUMMARY Calcium signaling and homeostasis in spermatozoa is essential for successful fertilization. The overall goal of this research program is to elucidate how sperm CatSper channel assembles to form Ca2+ signaling nanodomains and integrates proteolytic and metabolic pathways to control mammalian sperm motility and fertility. The research program aims to understand how calcium signaling and homeostasis in sperm is crucial for suc- cessful fertilization, specifically focusing on the CatSper channel and its crosstalk with other signaling pathways. During the first funding cycle, significant progress has been made in comprehending CatSper's role in sperm motility and fertility. Molecular and structural organization, along with new CatSper components, were identified through proteomic screens. In-depth studies using mouse models shed light on the channel's activity, assembly, and trafficking. Additionally, 3D in situ molecular imaging revealed CATSPER1 as a molecular signature of suc- cessful sperm reaching the fertilization site. Cryo-electron tomography further allowed the resolution of the first in-cell CatSper structure in human and mouse sperm flagella, contributing to a clearer understanding of the channel's composition and spatial arrangement. This R01 renewal builds on new CatSper components identified, new animal models generated with novel strat- egies, and new cutting-edge imaging techniques acquired during this period. Our studies reveal many unex- pected features and broader implications of CatSper regulation of mammalian sperm physiology and fertilization, laying the groundwork. We pursue the same long-term goals of deepening our understanding of sperm physiol- ogy and uncovering new pathways that could be exploited to assess and control sperm motility and fertility with new Specific Aims investigating 1] the role of ancillary transmembrane subunits in regulating channel assembly and nanodomain organization; 2] the proteolytic regulation of the channel, and 3] its physiological significance on the sperm energy metabolism, sperm motility and fertility. Collectively, these new aims, leveraging work from the first R01, will elucidate the entirely novel molecular mechanisms by which CatSper maintain and terminate sperm motility. This new knowledge will inspire im- provements sperm selection in assisted reproduction and provide new targets for contraceptive development.
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