Sex determination is the process that establishes whether an embryo will become male or female. Sex determination and the resulting sexual differentiation are fundamental aspects of normal development, and they profoundly shape the anatomy, physiology, and behavior of nearly all animal species. Moreover, disorders of sexual differentiation (DSDs) are among the most common congenital syndromes and often have serious medical and social consequences. Research in the Zarkower laboratory aims to uncover the molecular and genetic mechanisms that underlie sexual development. To accomplish this goal we study sexual development in the mouse, where powerful genetic, genomic, and molecular approaches are possible and much of the biology is similar to that of humans.
Our work focuses largely on a family of genes we discovered that are widely conserved in sexual development. One of these, DMRT1, maps to a short region of human chromosome 9 that is required for male development. We made a mouse "knockout" of Dmrt1 and found that it causes testis defects similar to those of humans with deletions of chromosome 9. Much evidence has implicated Dmrt1 and its close homologs in vertebrate sex determination, in birds, reptiles, fish, and amphibians. Recently we found that the sexual identify of cells in the gonad has to be actively maintained even in adults, and that disrupting this maintenance can cause cells to “switch” sex through a process of cell fate reprogramming. To better understand how gonadal cell fates are controlled we are using genomic approaches including ChIP-seq, Hi-ChIP and expression profiling, coupled with conditional gene targeting and structural biology. This work is ongoing but has already yielded important insights into testicular germ cell cancer, germ line stem cells, cell fate reprogramming, and regulation of meiosis.
Nakagawa T, Zhang T*, Kushi R, Nakano S, Endo T, Nakagawa M, Yanagihara N, Zarkower D., Nakayama K. (2017) Regulation of mitosis-meiosis transition by the ubiquitin ligase β-TrCP in male germ cells. Development 144(22):4137-4147.
Zhang T, Oatley J, Bardwell VJ, and Zarkower D. (2016) DMRT1 Is Required for Mouse Spermatogonial Stem Cell Maintenance and Replenishment. PLoS Genet. 12(9):e1006293.
Murphy, M.W., Lee, J.K., Rojo, S., Gearhart, M.D., Kurahashi, K., Banerjee, S., Loeuille, G.-A., Bashamboo, A., McElreavey, K., Zarkower, D., Aihara, H., and Bardwell, V.J. (2015) An ancient protein-DNA interaction underlying metazoan sex determination. Nature Structural and Molecular Biology 22:442-451.
Gamble, T., Coryell, J., Ezaz, T., Lynch, J., Scantlebury, D.P., and Zarkower, D. (2015) Restriction site-associated DNA sequencing (RAD-seq) reveals an extraordinary number of transitions among gecko sex-determining systems. Molecular Biology of Evolution, 32:1296-1309.
Lindeman, R.E., Gearhart, M.D., Minkina, A., Bardwell, V.J., and Zarkower, D. (2015) Sexual cell fate reprogramming in the ovary by DMRT1. Current Biology 16:764-771.
Zhang, T., Murphy, M.W., Gearhart., M.D., Bardwell, V.J., and Zarkower, D. (2014) The mammalian Doublesex homolog DMRT6 coordinates the transition between mitotic and meiotic developmental programs during spermatogenesis. Development 141:3662-3671.
Minkina A, Matson CK, Lindeman RE, Ghyselinck NB, Bardwell VJ, Zarkower D. DMRT1 protects male gonadal cells from retinoid-dependent sexual transdifferentiation. Developmental Cell. 2014 Jun 9;29(5):511-20.
Matson CK, Murphy MW, Sarver AL, Griswold MD, Bardwell VJ, Zarkower D. DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature. 2011 Jul 20;476(7358):101-4.
Raymond, C.S., C. Shamu, M.M. Shen, K. Seifert, B. Hirsch, J.Hodgkin, and D. Zarkower (1998). Evidence for evolutionary conservation of sex-determining genes. Nature 391:691-695.