The broad, long-term objective of the present application is to study a novel regulatory pathway of gene expression in mouse spermiogenesis that could be exploited for development of novel male contraceptives. Spermiogenesis is a complex differentiation process by which haploid germ cells transform into mature spermatozoa. In the past few years, genetic studies in mice have identified four genes that cause a global arrest in early spermiogenesis when deleted in mice, and these genes constitute a group of key regulators of spermiogenesis (CREM, TRF2, MIWI, and TPAP). In this project, we will characterize a novel key regulator of spermiogenesis named RNF17 in mice.
Our specific aims are: 1) Knockout mice will be generated and characterized to study the regulation of spermiogenesis; 2) Proteins interacting with the novel key regulator will be screened using the yeast 2-hybrid system, and will be characterized biochemically and cell biologically; 3) Genes transcriptionally regulated by the novel key regulator will be identified by the gene array technology using both the Affymetrix mouse gene chips and our own germ cell microarrays. Our ? proposed genetic, biochemical and genomics experiments will define a novel regulatory network of gene expression in mouse spermiogenesis, will have implications in molecular etiology of male infertility in humans, and will provide critical information about regulation of spermiogenesis that could be explored for developing reversible male contraceptive leads with minimal side effects. ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HD045866-05
Application #
7333280
Study Section
Special Emphasis Panel (ZHD1-DRG-D (28))
Program Officer
Blithe, Diana
Project Start
2003-12-01
Project End
2008-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
5
Fiscal Year
2008
Total Cost
$303,114
Indirect Cost
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Yang, Fang; Eckardt, Sigrid; Leu, N Adrian et al. (2008) Mouse TEX15 is essential for DNA double-strand break repair and chromosomal synapsis during male meiosis. J Cell Biol 180:673-9
Cheng, Yong; Buffone, Mariano G; Kouadio, Martin et al. (2007) Abnormal sperm in mice lacking the Taf7l gene. Mol Cell Biol 27:2582-9
Yang, Fang; Skaletsky, Helen; Wang, P Jeremy (2007) Ubl4b, an X-derived retrogene, is specifically expressed in post-meiotic germ cells in mammals. Gene Expr Patterns 7:131-6
Wang, P Jeremy; Pan, Jieyan (2007) The role of spermatogonially expressed germ cell-specific genes in mammalian meiosis. Chromosome Res 15:623-32
Yang, Fang; De La Fuente, Rabindranath; Leu, N Adrian et al. (2006) Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis. J Cell Biol 173:497-507
Pan, Jieyan; Goodheart, Mary; Chuma, Shinichiro et al. (2005) RNF17, a component of the mammalian germ cell nuage, is essential for spermiogenesis. Development 132:4029-39
Wang, P Jeremy; Page, David C; McCarrey, John R (2005) Differential expression of sex-linked and autosomal germ-cell-specific genes during spermatogenesis in the mouse. Hum Mol Genet 14:2911-8