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.
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.
|Luo, Mengcheng; Zhou, Jian; Leu, N Adrian et al. (2015) Polycomb protein SCML2 associates with USP7 and counteracts histone H2A ubiquitination in the XY chromatin during male meiosis. PLoS Genet 11:e1004954|
|Yang, Fang; Silber, Sherman; Leu, N Adrian et al. (2015) TEX11 is mutated in infertile men with azoospermia and regulates genome-wide recombination rates in mouse. EMBO Mol Med 7:1198-210|
|Zhou, Jian; Stein, Paula; Leu, N Adrian et al. (2015) Accelerated reproductive aging in females lacking a novel centromere protein SYCP2L. Hum Mol Genet 24:6505-14|
|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|
|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; 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|
|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|
|Berkowitz, Karen M; Sowash, Aislinn R; Koenig, Lydia R et al. (2012) Disruption of CHTF18 causes defective meiotic recombination in male mice. PLoS Genet 8:e1002996|
|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|
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