The long-term objective of the current application is to study the regulation of chromosomal synapsis in mice by novel protein complexes recently identified in our laboratory. Abnormality in meiosis is a leading cause of birth defects and infertility in humans. Chromosomal synapsis is facilitated by the attachment of meiotic chromosome ends (telomeres) to the nuclear envelope and by rapid movements of meiotic chromosomes during early prophase I. While actin cytoskeleton is essential for dynamic movements of meiotic chromosomes in budding yeast, the nature of the actin-dependent motive force responsible for chromosome movement in any organism is not yet understood. We previously identified Tex19 as a germ cell-specific gene in mice that encodes a small protein (351 aa) of unknown function. Now we have found that TEX19 regulates chromosomal synapsis. We have also found that TEX19 forms a tight complex with ubiquitin E3 ligase UBR2, an ubiquitin E3 ligase of the N-end rule proteolysis pathway, and actin motor protein myosin II in the testis. Therefore, we hypothesize that TEX19 modulates meiotic chromosome movement and chromosomal synapsis through its association with ubiquitin E3 ligase UBR2 and the actin motor protein myosin II. We propose to test this hypothesis through the following experimental strategies.
In Specific Aim 1, we will investigate the molecular mechanisms by which TEX19-UBR2 and TEX19-myosin II complexes regulate chromosomal synapsis.
In Specific Aim 2, we plan to elucidate the role of the actin motor protein myosin II and actin filaments in meiotic chromosomal synapsis and chromosome movements through genetic and time-lapse imaging analyses. An innovative combination of biochemical, genetic, cell biological, and time-lapse imaging approaches will provide insights into the mechanisms underlying the regulation of meiotic chromosome movements in mice, which has remained largely unexplored.

Public Health Relevance

Abnormalities in meiosis are a leading cause of both infertility and birth defects (trisomy and monosomy) in humans. Completion of this project will provide insight into the etiology of male infertility and birth defects in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM089893-03
Application #
8260559
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Janes, Daniel E
Project Start
2010-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$300,960
Indirect Cost
$112,860
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
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