David Zarkower, PhD
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 affect 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 consequences. Research in the Zarkower laboratory aims to uncover the molecular and genetic mechanisms underlying sex determination and sexual differentiation. To accomplish this goal we study several model organisms in which powerful genetic and molecular approaches are possible, primarily the nematode worm C. elegans and the mouse.
In C. elegans we are interested in the master regulator of sexual differentiation Transformer 1 (TRA-1), which controls all aspects of sexual development, and we have used genome-wide ChIP-seq methods to identify the genes TRA-1 controls. One example is male abnormal 3 (mab-3), which is required for several aspects of male development and behavior. mab-3 is related to a fruit fly sex-determining gene called doublesex. Both genes share the "DM domain" DNA binding motif, a similarity that provided the first evidence that sex determination is a deeply conserved process. In C. elegans we also have developed methods to isolate the two precursor cells that give rise to the gonad and profile their mRNA expression, which is helping reveal how the development of this reproductive organ is controlled.
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. Much recent evidence also has implicated Dmrt1 and its close homologs in sex determination in birds, reptiles, fish, and amphibians. We made a mouse "knockout" of Dmrt1 and found that it causes testis defects similar to those of humans with chromosome 9 deletions. We are using genomic approaches including ChIP-seq and RNA-seq, coupled with conditional gene targeting 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.
A new research area for the lab is the evolution of vertebrate sex chromosomes. As a model we have focused on geckos, a large vertebrate group (1400 species) in which new sex-determining mechanisms have evolved many times. We are combining sophisticated genome analysis methods with phylogenetic approaches to find transitions between sex determination mechanisms and identify the chromosomes and genes involved. This will shed important light on chromosome evolution and the origins of vertebrate sex determination.
Sex and the singular DM domain: insights into sexual regulation, evolution and plasticity. Matson CK, and Zarkower D (2012) Nat Rev Genet, in press.
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
DMRT1 promotes oogenesis by transcriptional activation of Stra8 in the mammalian fetal ovary. Krentz AD, Murphy MW, Sarver AL, Griswold MD, Bardwell VJ, Zarkower D. Dev Biol. 2011 356:63-70. PMID: 21621532
MPK-1 ERK Controls Membrane Organization in C. elegans Oogenesis via a Sex-Determination Module. (2011) Arur S, Ohmachi M, Berkseth M, Nayak S, Hansen D, Zarkower D, Schedl T., Developmental Cell 20:677-88.
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) Developmental Cell 19:612-24. PMCID: NIHMS245606
Genome-wide analysis of DNA binding and transcriptional regulation by the mammalian Doublesex homolog DMRT1 in the juvenile testis.Murphy, M.W., Sarver, A..L, Rice, D., Hatzi, K,, Ye, K., Melnick, A., Heckert, L.L., Zarkower, D., and Bardwell, V.J. (2010) Proc. Natl. Acad. Sci. USA 201:13360-5. PMCID: PMC2922116
Functional genomic identification of genes required for male gonadal differentiation in C. elegans. Kalis, A.K., Kroetz, M.B., Larson, K.M. and Zarkower, D. (2010) Genetics 185:523-535.
EGL-5/ABD-B plays an instructive role in male cell fate determination in the C. elegans somatic gonad. Kalis, A.K., Murphy, M.W., and Zarkower, D. (2010) Dev. Biol. 344:827-835.
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 U S A 106:22323-8.
Somatic sexual differentiation in Caenorhabditis elegans.(2008) Wolff JR and Zarkower, D. Current Topics in Developmental Biology. 200883:1-39
A mammal-specific Doublesex homolog required for sex chromatin modification during male meiosis.(2007) Kim, S., Namekawa, S.H., Niswander, L.M., Ward, J.O., Lee, J.T., Bardwell, V.J., and Zarkower, D. PLoS Genetics 3:e62.
Mice mutant for the DM domain gene Dmrt4 are viable and fertile but have polyovular follicles.(2006) Balciuniene, J., Bardwell, V.J., and Zarkower D. Mol. Cell. Biol. 26:9884-8991.
The DM domain protein MAB-3 promotes sex-specific neurogenesis in C. elegans by regulating bHLH proteins.(2005) Ross, J.M., Kalis, A., and D. Zarkower. Developmental Cell 8:881-892
A forkhead protein controls sexual identity of the C. elegans male gonad.(2004) Chang W, Tilmann C, Thoemke K, Markussen F-H, Mathies LD, Kimble J, and Zarkower D. Development 131: 1425-1436.
Polycomb group regulation of Hox gene expression in C. elegans.(2003) Ross, J., and Zarkower, D. Developmental Cell 4:891-901.
Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation.(2000) Raymond, C.S., Murphy, M.W., O'Sullivan, M.G., Bardwell, V.J., and Zarkower, D. Genes Dev. 14:2587-2595.
mab-3 is a direct tra-1 target gene regulating diverse aspects of C. elegans male sexual development and behavior.(2000) Yi, W., Ross, J.M., and Zarkower, D. Development 127:4469-4480.
Similarity of DNA binding and transcriptional regulation by C. elegans MAB-3 and Drosophila melanogaster DSX suggests conservation of sex determining mechanisms. (1999) Yi, W, and D. Zarkower. Development 126:873-881.
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.
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