Penn Veterinary Medicine | University of Pennsylvania

Description of Research Expertise

Research Interests
Regulation of meiosis, DNA recombination, chromosome segregation, DNA double-strand break repair, chromosome synapsis, male contraception, male infertility in humans, molecular biology and genetics of spermatogonial stem cells.

Key words: spermatogonial stem cells, meiosis, homologous recombination, synaptonemal complex, synapsis, spermiogenesis, and male infertility

Description of Research
Our group focuses on the study of germline stem cell development and meiosis in mice and humans. Because of the presence of a fascinating population of adult stem cells, men produce sperm through their lifetime. Meiosis, a cell division unique to germ cells, allows the reciprocal exchange of genetic material between paternal and maternal genomes. Our research interests include molecular genetics of spermatogonial stem cell renewal vs. differentiation, chromosomal synapsis, DNA double-strand break repair, homologous recombination, genetic causes of male infertility in humans, and male contraception. Functional characterization of a number of new genes in our laboratory has uncovered novel regulatory mechanisms underlying key biological processes unique to germ cells. On one hand, our studies provide molecular insights into the development of germ cells in mice. On the other hand, these mouse studies have important implications for understanding the genetic causes of male infertility in humans and developing novel male contraceptives.

Spermatogonia – Adult Germline Stem Cells

Spermatogonia are the self-renewing, mitotic germ cells of the testis. We previously identified more than thirty germ-cell-specific genes from mouse spermatogonia in a genomic screen. We are interested in interrogating the spermatogonial stem cell renewal vs. differentiation using molecular genetics, in vitro expansion, and in vivo transplantation approaches. We have recently found that LIN28 (aka TEX17) specifically marks undifferentiated spermatogonia in mice and, furthermore, that the population of undifferentiated spermatogonia can be cytologically divided into two subpopulations: Ngn3-GFP-negative (high stem cell potential) and Ngn3-GFP-positive (high differentiation commitment).

The X chromosome and Male Infertility

We have identified TEX11 as the first X chromosome-encoded meiosis-specific factor in mammals. In principle, meiosis-specific genes could be located anywhere in the genome. However, no mouse sex chromosome-linked mutants with meiosis-specific defects had been reported, leading to the perception that meiosis-specific factors are rarely if ever encoded by the sex chromosomes. We were the first to clone Tex11, an X-linked germ cell-specific gene. In a recent study, by ablating the function of Tex11 in mice, we have demonstrated that Tex11 is essential for meiosis and fertility in males. Our findings have important implications for male infertility in humans, which accounts for about half of the cases of infertility among couples. An estimated 15% of couples are affected by infertility worldwide. Given that disruption of Tex11 causes azoospermia in mice, we surmise that mutations in the human TEX11 gene could be found in infertile men.

Regulation of Homologous Recombination

During meiosis, homologous chromosomes undergo synapsis and recombination. The arrangement of homologous chromosomes is tightly regulated by the synaptonemal complex (SC). SYCP2 is an integral component of SCs in mammals. Our genetic and cell biological studies demonstrate that SYCP2 is required for the formation of SCs and chromosomal synapsis. We also find that TEX11 interacts with SYCP2 and is a novel constituent of meiotic nodules involved in recombination. TEX11 promotes both synapsis and recombination, and thus may provide a physical link between these two fundamental meiotic processes. Additionally, we identify TEX15 as a novel meiosis-specific factor that functions earlier than TEX11 during meiotic recombination. In parallel with BRCA1 and BRCA2, TEX15 plays an essential role in the DNA repair pathway that regulates the loading of DNA repair proteins (RAD51/DMC1) onto sites of double strand breaks. We plan to further elucidate the role of these meiosis-specific factors in the regulation of homologous recombination.

Selected Publications

Pan J, Eckardt S, Leu NA, Buffone MG, Zhou J, Gerton GL, McLaughlin KJ, Wang PJ.: Inactivation of Nxf2 causes defects in male meiosis and age-dependent depletion of spermatogonia. Dev Biol 330(1): 167-174, 2009.

Zheng K, Wu X, Kaestner KH, Wang PJ.: The pluripotency factor LIN28 marks undifferentiated spermatogonia in mouse. BMC Dev Biol. 9(1): 38, 2009.

Yang F., Gell K., van der Heijden G.W., Eckardt S., Leu N.A., Page D.C., Benavente R., Her C., Höög C., McLaughlin K.J., Wang P.J.: Meiotic failure in male mice lacking an X-linked factor Genes Dev 22: 682-691, 2008.

Yang F, Eckardt S, Leu NA, McLaughlin KJ, Wang PJ.: Mouse TEX15 is essential for DNA double-strand break repair and chromosomal synapsis during male meiosis. J. Cell Biol. 180(4): 673-679, 2008.

Cheng, Y, Buffone, MG, Kouadio, M, Goodheart, M, Page, DC, Gerton, GL, Davidson, I, Wang, PJ: Abnormal sperm in mice lacking the Taf7l gene Mol. Cell. Biol. 27(7): 2582-2589, 2007.

Yang F., De La Fuente R., Leu N.A., Baumann C., McLaughlin K.J., and Wang P.J.: Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis J. Cell Biol. 173(4): 497-507, 2006.

Wang P.J., Page D.C. and McCarrey J.R.: Differential expression of sex-linked and autosomal germ-cell-specific genes during spermatogenesis in the mouse Hum. Mol. Genet 14: 2911-2918, 2005.

Pan J., Goodheart M., Chuma S., Nakatsuji N., Page D.C., and Wang P.J.: RNF17, a component of the mammalian germ cell nuage, is essential for spermiogenesis Development 132: 4029-4039, 2005.

Yang, J., Bogerd, H.P., Wang, P.J., Page, D.C. and Cullen, B.R.: Two closely related human nuclear export factors utilize entirely distinct export pathways. Mol. Cell 8: 397-406, 2001.

Wang, P.J., McCarrey, J.R., Yang, F. and Page, D.C.: An abundance of X-linked genes expressed in spermatogonia. Nat. Genetics 27: 422-426, 2001.