Sex determination is the process that establishes whether an embryo will differentiate into a male or a female. Sex determination and sexual differentiation profoundly shape the anatomy, physiology, and behavior of nearly all animal species. Moreover, disorders of sexual differentiation (DSDs) are common congenital syndromes that can have serious medical and social consequences. The Zarkower laboratory seeks to uncover the molecular and genetic mechanisms that underlie sex determination, sexual differentiation, and the maintenance and reprogramming of sexual cell fates.
Our work is focused particularly on DMRT transcription factors, deeply conserved genes that regulate sexual development in most multicellular animals. One of these, DMRT1, regulates sex determination and gonadal development in many vertebrates. We are using genomic approaches coupled with conditional gene targeting to understand how DMRT1 controls testis development in the mouse and to identify the genes regulated by DMRT1. This work is ongoing but has already yielded a number of insights and surprises, including the finding that cells in the mammalian testis must be continually instructed to remain male, even in adulthood, or they will transdifferentiate into their female equivalents.
A newer area of research in the lab is evolution of vertebrate sex chromosomes. We focuse mainly on geckos, a large vertebrate group (~1500 species) in which new sex determining mechanisms have evolved multiple times. We combine next-generation sequencing approaches with cytogenetics and phylogenetic analysis to identify transitions between sex determination mechanisms and identify the chromosomes and genes involved. This work is shedding light on chromosome evolution and origins of vertebrate sex determination.
Selected Publications (Pubmed Search)
Minkina A, Matson CK, Lindeman RE, Ghyselinck NB, Bardwell VJ, and Zarkower D. (2014) DMRT1 Protects Male Gonadal Cells from Retinoid-Dependent Sexual Transdifferentiation. Developmental Cell 9:511-520.
Gamble, T, Geneva, TJ, Glor, RE, and Zarkower D. (2014) Anolis sex chromosomes are derived from a single ancestral pair. Evolution 4:1027-1041.
Berkseth M, Ikegami K, Arur S, Lieb JD, and Zarkower D. (2013) TRA-1 ChIP-seq reveals regulators of sexual differentiation and multilevel feedback in nematode sex determination. Proc Natl Acad Sci U S A. 110:16033-8.
Matson CK, and Zarkower D. (2012) Sex and the singular DM domain: insights into sexual regulation, evolution and plasticity. Nature Reviews Genetics 13:163-174
Matson CK, Murphy MW, Sarver AL, Griswold MD, Bardwell VJ, and Zarkower D. (2011) DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature. 476:101-104
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.
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. (2009) The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency. Proc. Natl. Acad. Sci USA 106:22323-8.
Raymond, C.S., Shamu, C.E., Shen, M.M., Seifert, K.J., Hirsch, B., Hodgkin, J., and D. Zarkower (1998) Evidence for evolutionary conservation of sex determining genes. Nature 391:691-695.