Debra J. Wolgemuth, PhD
Genetic control of mammalian germ cell differentiation.
The research interests of the Wolgemuth lab focus on understanding the genetic control of gametogenesis and embryogenesis using mouse models and gene targeting, transgenic, and molecular and cell biological approaches. The first of the three major projects involves understanding the function of the A and E-type cyclins during the mitotic and meiotic cell cycles mainly during spermatogenesis but also in oogenesis. We have demonstrated that cyclin A1 is essential for the progression of spermatocytes into the first meiotic division, that cyclin A2 is required for mitotic divisions of male germ cell stem cells, and that the E-type cyclins have unexpected function during meiosis, notably in the maintenance of telomere integrity. A second area of research involves elucidating the function of the BET family of double bromodomain-containing proteins, proteins that read epigenetic marks, during germ cell differentiation and neural development. We showed that the BET family member BRDT is essential for proper chromatin remodeling and transcriptional regulation during meiotic prophase and also during spermiogenesis and that BRD2 is essential for embryonic survival and neural differentiation and function, in particular in the etiology of seizure susceptibility. We have recently generated a conditional knockout model of Brd2 which will allow us to determine its function in adult tissues, including the germ line. Finally, the lab is pursuing studies on the role of retinoid signaling during male germ cell differentiation, again in using molecular genetic approaches in the mouse model, and more recently, pharmacologic intervention. We have used a pan-antagonist of the retinoic acid receptors (RARs) to disrupt spermatogenesis and induce sterility, importantly in a reversible manner. Long-term efforts of this project will involve developing RAR-alpha selective antagonists, identifying the target genes of RAR-alpha, and determining their function in germ cell-Sertoli cell interactions.
Liu, D., M.M. Matzuk, W.K. Sung, Q. Guo, P. Wang and D.J. Wolgemuth. (1998). Cyclin A1 is required for meiosis in the male mouse. Nat. Genet. 20, 377-380. [No PMCID; PMID: 9843212].
Liu, D., C. Liao and D.J. Wolgemuth. (2000). A role for cyclin A1 in the activation of MPF and G2-M transition during meiosis of male germ cells in mice. Dev. Biol. 224, 388-400. [No PMCID; PMID: 10926775].
Liao, C., X.Y. Wang, H.Q. Wei, S.Q. Li, T. Merghoub, P.P. Pandolfi and D.J. Wolgemuth. (2001). Altered myelopoiesis and the development of acute myeloid leukemia in transgenic mice overexpressing cyclin A1. Proc. Natl. Acad. Sci. U.S.A. 98, 6853-6858. [PMCID: 34442; PMID: 11381140].
Chung, S.S., W. Sung, X.Y. Wang and D.J. Wolgemuth. (2004). Retinoic acid receptor alpha is required for synchronization of spermatogenic cycles and its absence results in progressive breakdown of the spermatogenic process. Dev. Dyn. 230, 754-766. [PMCID: 3785309; PMID: 15254909].
Chung, S.S., X.Y. Wang and D.J. Wolgemuth. (2005). Male sterility in mice lacking retinoic acid receptor alpha involves specific abnormalities in spermiogenesis. Differentiation. 73, 188-198. [PMCID: 3785313; PMID: 15901285].