Worldwide, couples want to manage their own reproduction and there is great need for more diverse contraceptives, especially ones targeted to aspects of male reproduction. Understanding causes of male infertility will likely aid in identification of suitable contraceptive targets. At The Jackson Laboratory, the ReproGenomics Program uses whole-genome ENU [N-ethyl-N-nitrosourea] mutagenesis to induce random mutations in the mouse genome and screens for mutants exhibiting infertility. A new mutation identified in this program, ferf1 (fertilization failure 1), is the subject of this proposal. Affected males are normal with respect to many parameters (body weight, sexual behavior, sperm count and morphology). The phenotype of the ferf1 mutation is breeding failure. Furthermore, during fertilization in vitro, sperm from affected males show abnormal agglutination and fail to fertilize zona pellucida-enclosed oocytes, although they do fertilize and activate zona-free oocytes. Knowledge of the protein encoded by the ferf1 gene could yield insight into poorly understood steps in sperm capacitation and fertilization and possibly identify a novel contraceptive target. The protein affected by the ferf1 mutation could be one synthesized in the germ cells. Alternatively, it could be secreted from somatic cells, perhaps the epididymis, and coat the sperm, thereby affecting their ability to become capacitated and their success in fertilization. The goals in Aim 1 are to determine the phenotypic characteristics of ferf1 sperm after their release from the epididymis to their interaction with the acolyte's zona pellucida and to determine, by epididymal fluid switching experiments, if the abnormal agglutination characteristics and fertilization phenotype of ferf1 sperm are inherent to the sperm or to male reproductive tract secretions. The goal of Aim 2 is to create a high-resolution genetic map surrounding the ferf1 gene and, ultimately, to positionally clone and identify the gene interrupted by the ferf1 mutation. The phenotype of the ferf1 mutation impacts important steps in fertilization, could provide insight into male infertility, and may even identify a promising contraceptive target. Thus, an expeditious and focused attack over a relatively short funding period is desirable to bring the project to the point of setting priorities for future research and development of the concept.
