Sexual development 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 aimed to uncover the molecular and genetic mechanisms that underlie sexual development. We studied several animals, including the nematodes, with their speedy genetics and molecular genetics, mice, where powerful genetic, genomic, and molecular approaches are possible and much of the biology is similar to that of humans, and geckos, which have undergone particularly rapid evolution of sex determination. Much of our work focused on a family of genes we first found in C. elegans, the so-called DM domain transcription factor genes. Two discoveries have particularly stood out. First, we found that DM domain genes are widely conserved in sexual development across metazoan animals. Second, we found that the sexual identify of cells in the mammalian gonad has to be actively maintained by DMRT1 and other genes, even in adults, and that disrupting this maintenance can cause cells to “switch” sex through a process of sexual cell fate reprogramming, or sexual transdifferentiation. The DM domain genes also provided many insights into germ line stem cells, regulation of the mitosis/meiosis switch, sex-specific nervous system development and other important aspects of reproductive biology.
Selected Publications: PubMed Search
Lindeman, RE, Murphy, MW, Agrimson, KS, Gewiss, RL, Bardwell, VJ, Gearhart, MD, Zarkower, D (2021) The conserved sex regulator DMRT1 recruits SOX9 in sexual cell fate reprogramming. Nucleic Acids Research 49:6144-6164
Weinberg P, Berkseth M, Zarkower D, Hobert O. (2018) Sexually Dimorphic unc-6/Netrin Expression Controls Sex-Specific Maintenance of Synaptic Connectivity. Current Biology 28:623-629
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.
Matson, C.K., Murphy, M.W., Griswold, M.D., Yoshida, S., Bardwell, V.J., and Zarkower, D. (2010) The mammalian Doublesex homolog DMRT1 is a transcriptional gatekeeper that controls the mitosis versus meiosis decision in male germ cells. Developmental Cell 19:612-24.
Ross, J.M., Kalis, A., and D. Zarkower. (2005) The DM domain protein MAB-3 promotes sex-specific neurogenesis in C. elegans by regulating bHLH proteins. Developmental Cell 8:881-892
Raymond, C.S., Murphy, M, O’Sullivan, M.G., Bardwell, V.J., and D. Zarkower (2000). Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation. Genes & Development 14:2587-2595.
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.