The long-term objective of this application is to understand the regulation of meiosis in mice and humans by evolutionarily conserved protein networks. Infertility is a worldwide reproductive health problem affecting men and women about equally. Genetic studies in various model organisms have elucidated the molecular pathways underlying the regulation of fertility. In particular, more than 400 mouse mutants have infertility as a major phenotype. Despite the rapid progress made in model organisms, little progress has been made in translating these findings into identifying genetic causes of infertility in humans. This lack of progress can be attributed to two critical barriers: 1) causative mutations in a particular gene are expected to be extremely rare and 2) causality is nearly impossible to prove for infertility, as traditional pedigree-based linkage analyses are not applicable, due to the lack of offspring. As such, it is clear that new concepts and innovative approaches are required to evaluate genetic causes of human male infertility. The current application is to investigate the role of TEX11, an X chromosome-encoded factor, in regulating fertility in both mice and humans. Our previous studies in mice have shown that TEX11 interacts with SYCP2, an integral component of the synaptonemal complex, and is a novel constituent of meiotic recombination nodules. Moreover, we have shown that TEX11 plays a dual function in meiosis: chromosomal synapsis and crossover formation. Finally, our genetic studies in humans have identified a number of TEX11 mutations in infertile men, supporting its role in male infertility in humans. In this proposal, we will utilize a novel and powerful knockin strategy to generate and characterize mice bearing mutations analogous to infertility-associated mutations in humans to rapidly advance our knowledge of the genetic basis of human male infertility.
Our specific aims are: 1) to determine whether TEX11 is a hot spot for mutations causing infertility in men by modeling human diseases in mice;2) to determine the threshold of TEX11 protein that is required for meiosis;3) to identify TEX11-assoicated proteins systematically and probe their functions in meiosis. Together, our studies will elucidate the TEX11-dependent mechanisms underlying the regulation of meiosis in both mice and humans, and provide insight into the molecular etiology of X-linked male infertility in humans.

Public Health Relevance

Abnormalities in meiosis are leading causes of infertility and birth defects in humans. Completion of this project will identify genetic causes of X-linked male infertility in humans and improve genetic counseling to patients seeking infertility treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM076327-06
Application #
8469512
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Haynes, Susan R
Project Start
2007-09-20
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$308,800
Indirect Cost
$115,800
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zhou, Jian; Goldberg, Ethan M; Leu, N Adrian et al. (2014) Respiratory failure, cleft palate and epilepsy in the mouse model of human Xq22.1 deletion syndrome. Hum Mol Genet 23:3823-9
Zhou, Jian; Leu, N Adrian; Eckardt, Sigrid et al. (2014) STK31/TDRD8, a germ cell-specific factor, is dispensable for reproduction in mice. PLoS One 9:e89471
Luo, Mengcheng; Yang, Fang; Leu, N Adrian et al. (2013) MEIOB exhibits single-stranded DNA-binding and exonuclease activities and is essential for meiotic recombination. Nat Commun 4:2788
Zhou, Jian; McCarrey, John R; Wang, P Jeremy (2013) A 1.1-Mb segmental deletion on the X chromosome causes meiotic failure in male mice. Biol Reprod 88:159
Zhou, Jian; Yang, Fang; Leu, N Adrian et al. (2012) MNS1 is essential for spermiogenesis and motile ciliary functions in mice. PLoS Genet 8:e1002516
Zhou, Jian; Pan, Jieyan; Eckardt, Sigrid et al. (2011) Nxf3 is expressed in Sertoli cells, but is dispensable for spermatogenesis. Mol Reprod Dev 78:241-9
Zheng, Ke; Xiol, Jordi; Reuter, Michael et al. (2010) Mouse MOV10L1 associates with Piwi proteins and is an essential component of the Piwi-interacting RNA (piRNA) pathway. Proc Natl Acad Sci U S A 107:11841-6
Zheng, Ke; Yang, Fang; Wang, Peijing Jeremy (2010) Regulation of male fertility by X-linked genes. J Androl 31:79-85
Yang, Fang; Cheng, Yong; An, Jee Young et al. (2010) The ubiquitin ligase Ubr2, a recognition E3 component of the N-end rule pathway, stabilizes Tex19.1 during spermatogenesis. PLoS One 5:e14017
Pan, Jieyan; Eckardt, Sigrid; Leu, N Adrian et al. (2009) Inactivation of Nxf2 causes defects in male meiosis and age-dependent depletion of spermatogonia. Dev Biol 330:167-74

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