The role of Cdyl and CDY in mammalian spermatogenesis
Massachusetts Institute of Technology. Dept. of Biology.
David C. Page.
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Mouse Cdyl was originally identified based on homology to the human gene CDY (Lahn and Page, 1999), which is found in four copies on the human Y chromosome (Kuroda-Kawaguchi et al., 2001). Because CDY is expressed specifically in the testis (Lahn and Page, 1999) and is found in Y chromosomal regions that are deleted in some infertile men (Kuroda-Kawaguchi et al., 2001), CDY is thought to have an important role in male fertility and spermatogenesis. However, human studies have not yet been able to directly implicate CDY in male infertility. Even though mouse Cdyl is not located on the Y chromosome, it is the closest known mouse homologue of human CDY and is expressed highly in the testes (Lahn and Page, 1999), which suggests that mouse Cdyl provides a suitable model for the study of human CDY function. However, unlike human CDY, mouse Cdyl is expressed in tissues other than the testis (Lahn and Page, 1999). We have generated mice deficient for Cdyl to study its role in spermatogenesis and characterized their phenotype on a pure BALB/c background. Nearly 2/3 of Cdyl knockout mice die shortly after birth, but those that survive to adulthood appear healthy except for spermatogenic defects.(cont.) Mice lacking Cdyl produce spermatozoa with misshapen heads and exhibit substantial germ cell death. The loss of germ cells is evident in some knockout mice as early as 3.5 weeks of age, affects spermatogonia, spermatocytes, and spermatids, and is so severe that at 5 months of age the seminiferous tubules of Cdyl knockout mice appear nearly empty. These results demonstrate that Cdyl plays a crucial role in spermatogenesis and suggest that the homologous human gene CDY does as well. However, our results do not support a previously suggested hypothesis that Cdyl participates in the global acetylation of histone H4 in spermatid nuclei (Lahn et al., 2002), as hyperacetylated histone H4 was detected in both wildtype and knockout spermatids. To directly study the role of the human gene CDYin spermatogenesis, we have attempted to rescue the Cdyl-/- spermatogenic phenotype by constructing a transgenic mouse that expresses human CDY and breeding the CDY transgene onto a Cdyl -/- background. Preliminary data from these crosses suggests that human CDY can not rescue the spermatogenic phenotype observed in Cdyl-/- mice, as Cdyl -/- TgCDY mice still exhibited germ cell loss.(cont.) However, we currently possess TgCDY mice only on a C57BL/6 background, and in the course of these rescue experiments we observed that the spermatogenic phenotype of Cdyl-l- mice is not as severe on a C57BL/6 background, on a mixed C57BL/6x129 background, or on a mixed C57BL/6xBALB/c background as it is on a pure BALB/c background. We believe that future studies, performed on a pure BALB/c background, will be able to better address whether human CDYcan rescue the Cdyl knockout mouse spermatogenic phenotype.
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2006.Includes bibliographical references (leaves 106-114).
DepartmentMassachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology