Grant: Operating Grant

Defects in spermatozoa, the cells that transfer the father's genetic material to an oocyte, underlie approximately half of all cases of infertility that are presented in the clinic. Spermatozoa are motile cells, and several unique structures in the sperm tail are believed to play important roles in motility. One of these structures is called the Outer Dense Fibers. Although these Outer Dense Fibers are present in sperm from fruit flies to man, their function is still unclear, but our recent evidence points to a role in sperm motility. However, several instances of abnormal sperm tail structures, including Outer Dense Fiber defects, have been reported in cases of human male infertility. It is not known what causes these defects. We had discovered and characterized many proteins in Outer Dense Fibers, as well as proteins that bind to these structures. For one of these, the abundant Odf2 protein, we recently developed two mouse models of male infertility. These mouse models show that this protein does not only play a role in sperm itself, but also -surprisingly- in the fertilized egg and embryo. Importantly, the mouse model shows sperm defects similar to what is observed in some cases of human male infertility. We propose to investigate these observations in detail, to establish the mechanisms of how this protein contributes to the normal Outer Dense Fibers and the sperm tail, and exactly how it contributes to the cell divisions in the fertilized egg. Our results may help explain the basis for some cases of human male infertility, and could be translated in future approaches to the clinic, by providing tools for diagnosis of male infertility involving ODF and axoneme defects and tests of a sperm's capability to fertilize an egg and support embryogenesis.