PARENT SESSION

(W360) SPERM DEFECTS IN MICE LACKING FUNCTION OF NIEMANN-PICK C1 PROTEIN.

Akabane, Hiroto¹, Graham, Stephanie¹, Richardson, Laura ², Zhu, Guo-Zhang¹, ¹ Marshall University, Huntington, WV² Marshall University School of Medicine, Huntington, WV

ABSTRACT- The Niemann-Pick C1 (NPC1) gene encodes for a multiple membrane spanning protein, which regulates the sorting and trafficking of low-density lipoprotein-mediated endocytosed cholesterol. Mutation of human NPC1 gene causes Niemann-Pick type C (NPC) disease, a fatal disorder characterized by progressive neurological degeneration and accumulation of abnormal amounts of cholesterol in certain endocytic organelles. The NPC1^NIH mice, a model of human NPC disease, bear a spontaneous mutation of NPC1 gene, and are infertile. In this study, we have performed sperm analysis to search for the cause of male NPC1^NIH mouse infertility. The number of sperm obtained from the cauda epididymis in NPC1(-/-) mice was decreased roughly three-and-half-fold of that in wild type mice. The decreased sperm number in NPC1(-/-) mice is due, at least in part, to partial degeneration of spermatogenesis in testes, as evidenced by histological analysis. Compared to wild type sperm, NPC1-deficient sperm showed a high frequency of morphological abnormalities, including tailless heads and aberrant heads. In in vitro fertilization assays using cumulus-intact eggs, NPC1-deficient sperm failed to produce two-cell embryos. Further analysis indicated that NPC1(-/-) sperm are dramatically crippled in adhesion to the egg zona pellucida, only 9.7% of the level of wild-type sperm. Moreover, about one-third of total cyritestin protein, a critical molecule for sperm binding to the egg zona pellucida, was not proteolytically processed on sperm from the cauda epididymis. Taken together, these results define that there are multiple sperm defects in mice with the loss function of NPC1 protein, and the observed sperm defects may contribute to the infertility of mutant male mice. (Supported by the NSF EPSCoR grant to Marshall University.)

KEY WORDS: niemann-pick c1 gene, gene mutation, sperm defect, infertility