The long-term goal of the current application is to elucidate novel molecular networks underlying mammalian meiosis and develop a mammalian cell culture system for in vitro meiosis. Meiosis, a process unique to germ cells, involves pairing synapsis, recombination, desynapsis, and segregation of homologous chromosomes. Genetic abnormalities resulting from meiosis are a leading cause of birth defects, pregnancy loss, and infertility in humans. The structural and functional properties of meiotic chromatin, which undergoes extensive reorganization, are undoubtedly the central themes of meiosis. Despite rapid progress in understanding meiosis, the complex interplay between chromatin organization and meiotic processes remains largely unexplored. In particular, the progress in understanding mammalian meiosis has lagged far behind meiotic studies in other model organisms, due to several critical barriers, including high cost, long duration, and the lack of sequence conservation of many meiosis-specific proteins across distant species. To overcome these roadblocks, we have developed cost-effective genomics and proteomics approaches to systematically identify a large number of uncharacterized mammalian meiosis factors. The current application will utilize an innovative combination of genetic, cell biological, and biochemical approaches to determine the role of our newly identified novel/uncharacterized factors and their interacting proteins in regulating meiotic recombination in mice. The proposed studies will focus on mechanistic insights into the regulation of meiotic recombination in three largely unknown or poorly understood aspects: second end capture, crossover formation, and homologous chromosome segregation. Progression through meiosis is a critical barrier to in vitro derivation of germ cells and a robust cell culture system for in vitro meiosis in multicellulr organisms remains elusive. Therefore, using a unique GFP reporter to monitor progression of meiosis in vitro, we plan to interrogate culture parameters in a stepwise manner to develop a cell culture-based in vitro meiosis system. Undoubtedly, development of an in vitro system for mammalian meiosis will not only drive basic mechanistic research on meiosis but also revolutionize regenerative medicine in the treatment of male infertility in humans.

Public Health Relevance

Abnormalities in meiosis are a leading cause of infertility, pregnancy loss, and birth defects (trisomy and monosomy) in humans. Completion of this project will provide insight into the etiology of birth defects and infertility in humans and potentially lead to development of treatment of infertility in humans.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZGM1)
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Melillo, Amanda A
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University of Pennsylvania
Schools of Veterinary Medicine
United States
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Shi, Baolu; Xue, Jiangyang; Zhou, Jian et al. (2018) MORC2B is essential for meiotic progression and fertility. PLoS Genet 14:e1007175
Kasowitz, Seth D; Ma, Jun; Anderson, Stephen J et al. (2018) Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development. PLoS Genet 14:e1007412
Kasowitz, Seth D; Luo, Mengcheng; Ma, Jun et al. (2017) Embryonic lethality and defective male germ cell development in mice lacking UTF1. Sci Rep 7:17259
Xu, Yang; Greenberg, Roger A; Schonbrunn, Ernst et al. (2017) Meiosis-specific proteins MEIOB and SPATA22 cooperatively associate with the single-stranded DNA-binding replication protein A complex and DNA double-strand breaks. Biol Reprod 96:1096-1104
Wang, P Jeremy (2017) Tracking LINE1 retrotransposition in the germline. Proc Natl Acad Sci U S A 114:7194-7196