Center for Reproductive
Department of Genetics & Development
Departement of Obstetrics & Gynecology
Training program in Genetics & Development
Cell Cycle Regulation during Gametogenesis
We have identified a novel mammalian A-type cyclin, cyclin Al, which we have shown to be expressed at highest levels if not exclusively in the testis in mice and humans. Targeted mutagenesis of the gene for cyclin A1 results in viable progeny but male sterility, while females are fully fertile. Cyclin A1-deficient male germ cells arrest at the G2/M transition of meiotic prophase I. The cells do not form haploid spermatids and rather, exhibit properties suggestive of a rapid entry into an apoptotic cell death. Our hypothesis is that there is a primary cell death response that is specifically activated in response to cell cycle arrest. We wish to understand the transcriptional control cyclin A1 in the male germ line, the kinase partners and substrates of cyclin A1 protein, and the functional redundancy of the two mammalian A-type cyclins. Our current projects include:
Cyclin A1 and Leukemogenesis
Cyclin A1 is highly expressed in human leukemic cells from patients with acute myeloid leukemia. To test the hypothesis that the aberrant high levels of cyclin A1 were causal in the leukemic phenotype, i.e., acting as an oncogene, we generated transgenic mice in which cyclin A1 was expressed under the direction of the human cathepsin G promoter in myeloid precursor cells. The transgenic animals exhibited abnormal myelopoiesis and developed acute myeloid leukemia. We have also recently observed high levels of cyclin A1 expression in testicular tumors of the highly invasive embryonal carcinoma class but not in the more common and less invasive seminoma. We propose that cyclin A1 represents a novel target for drug intervention in cancer therapy. Our current projects include:
Dietary retinal is required for spermatogenesis (and vision) in mammals. Studies generating mutations in specific receptors for vitamin A metabolites have clearly shown a role for the retinoid receptors RAR alpha and RXR beta in spermatogenesis. Our current projects include:
characterized some properties of
Fsrg1, a bromodomain-containing mouse gene that is homologous to the
gene female sterile homeotic. Fsrg1 is a member of a small
of bromodomain-containing genes that appear to be involved in chromatin
remodeling and possibly regulating transcription. Our current
Persson JL, Zhang Q, Wang XY, Ravnik SE, Muhlrad S, Wolgemuth, DJ (2005). Distinct roles for the mammalian A-type cyclins during oogenesis. Reproduction, 130(4): 411-422.
Chung SS, Wang X, Wolgemuth DJ (2005). Male sterility in mice lacking retinoic acid receptor alpha involves specific abnormalities in spermiogenesis. Differentiation, 73(4): 188-198.
Ekberg J, Landberg G, Holm C, Richter J, Wolgemuth DH, Persson JL (2004). Regulation of the cyclin A1 protein is associated with its differential subcellular localization in hematopoietic and leukemic cells. Oncogene, 23(56): 9082-9089.
Lele KM, Wolgemuth DH (2004). Distinct regions of the mouse cyclin A1 gene, Ccna1, confer male germ-cell specific expression enhancer funcation. Biol. Reprod, 71(4): 1340-1347.
Chaudry HW, Dashoush NH, Tang H, Zhang L, Wang X, Wu EX, Wolgemuth DJ (2004). Cyclin A2 mediates cardiomyocyte mitosis in the postmitotic myocardium. J. Biol. Chem, 279(34): 35858-35866.
Wolgemuth DJ, Lele KM, Jobanputra V, Salazar G (2004). The A-type cyclins and the meiotic cell cycle in male germ cells. Int J Androl, 27(4): 192-199. Review.