In most mammals, expression of a single dominant gene on the Y chromosome, SRY, directs differentiation of the bipotential embryonic gonads into testes and subsequent development of male characteristics. The biological role of other Y-linked genes is not fully understood, but deletion mapping strongly suggests that the majority are involved in spermatogenesis. In the mouse, nearly all known genes are clustered in the short arm of the Y chromosome (approximately 7Mb) and most proposed spermatogenesis genes are contained within approximately 1 Mb region defined by the Sxr b deletion interval. It is our working hypothesis that these genes will play a role in spermatogenesis and that each gene will be required at a specific stage such as mitosis, meiosis or sperm head development. The field has suffered by the difficulty of targeting Y genes and thus directly addressing their function. An alternative approach, of complimenting deleted genes in XOSxr b sex-reversed mice by BAC transgenesis, has recently demonstrated that the Y-linked eukaryotic translation initiation factor, Eif2s3y, is the spermatogonial proliferation factor, Spy, essential for post-natal mitotic proliferation of germ cells. Although useful, this model system is somewhat compromised by the absence of the other genes contained within Sxr b deletion and Yq. If the function of one gene is restored, absence of the other Sxr b genes that are expressed either before or after the complemented gene may prevent normal spermatogenesis. To overcome these limitations, we have recently developed a system to efficiently target genes on the Y chromosome. This proposal is designed to build on this progress and produce mice carrying null alleles of Eif2bs3y and Usp9y. These mice will then be used to directly determine the role played by these two Sxr genes in spermatogenesis.
