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 model organisms in which powerful genetic, genomic, and molecular approaches are possible, primarily the nematode worm C. elegans and the mouse.
In C. elegans we are interested in how the gonad differentiates into radically different structures in the two sexes and we have used cell-specific mRNA profiling to find genes expressed specifically in the two somatic gonad precursor cells and also expressed differently in the two sexes. We are now seeking to understand how these genes operate as a network to direct gonadal development in each sex.
We have identified a number of human and mouse genes that related to dsx and mab-3. 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 recent evidence has implicated Dmrt1 and its close homologs in vertebrate sex determination, in birds, reptiles, fish, and amphibians. We are using genomic approaches including ChIP-chip, ChIP-seq, and expression profiling, coupled with conditional gene targeting and structural biology to understand how DMRT1 controls testis development and to identify the genes regulated by DMRT1. This work is ongoing but has already yielded important insights into germ cell pluripotency, testicular germ cell cancer, cell fate reprogramming, and regulation of meiosis.
Selected Publications (Pubmed Search)
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.
DMRT1 Protects Male Gonadal Cells from Retinoid-Dependent Sexual Transdifferentiation. Minkina A, Matson CK, Lindeman RE, Ghyselinck NB, Bardwell VJ, Zarkower D. Dev. Cell. 2014 May 21. pii: S1534-5807(14)00237-8. doi: 10.1016/j.devcel.2014.04.017. [Epub ahead of print] PMID: 24856513
DMRT1 prevents female reprogramming in the postnatal mammalian testis. Matson CK, Murphy MW, Sarver AL, Griswold MD, Bardwell VJ, Zarkower D. Nature. 2011 476:101-104. PMID: 21775990
The mammalian Doublesex homolog DMRT1 is a transcriptional gatekeeper that controls the mitosis versus meiosis decision in male germ cells. Matson, C.K., Murphy, M.W., Griswold, M.D., Yoshida, S., Bardwell, V.J., and Zarkower, D. (2010) Dev. Cell 19:612-24. PMCID: NIHMS245606
The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency.(2009) Krentz, AD, Murphy, MW, Kim, S, Cook, MS, Capel, B, Zhu, R, Matin, A, Sarver, AL, Parker, KL, Griswold, MD, Looijenga, LH, Bardwell, VJ, and Zarkower, D. Proc. Natl. Acad. Sci USA 106:22323-8.
Evidence for evolutionary conservation of sex determining genes.(1998) Raymond, C.S., Shamu, C.E., Shen, M.M., Seifert, K.J., Hirsch, B., Hodgkin, J., and D. Zarkower. Nature 391:691-695.