Infertility is a major medical concern that affects about 1 of every 10 individuals of childbearing age worldwide. Although a significant proportion of infertility is accounted for by identifiable causes, the molecular basis of these defects is often not known or well characterized. Low sperm count in infertile men and ovulatory dysfunction and diminished ovarian function in infertile women are examples. It is becoming increasingly clear that many more disorders in medicine, including infertility, have a genetic basis than was previously realized. It is our goal to advance the field so that a better understanding of the underlying defects of infertility disorders will lead to improved treatments.
CTF18 encodes an evolutionarily conserved protein that is crucial for germline development in the fruitfly, and essential for the faithful transmission of chromosomes in yeast. We generated a mouse model that lacks Chtf18, the orthologue of the Drosophila melanogaster gene, cutlet. We demonstrated that gametogenesis and fertility are severely impaired in both Chtf18-/- male and female mice. We also showed that loss of Chtf18 results in premature separation of homologous chromosomes during meiosis. Consistent with these data is that while Chtf18-/- mice are to a large extent viable, loss of Chtf18 results in significant embryonic lethality. Defects in these processes are known to contribute greatly to causes of aneuploidy in offspring, and aneuploidy is one of the most frequent types of genetic defects that occur during reproduction. Our studies are designed to determine the roles CTF18/Chtf18 play in mammalian germ cell development and meiosis. We are examining the molecular mechanisms that control Chtf18 function in vivo, as well as the roles Chtf18 play in genome integrity of germ cells and somatic cells.
Better understanding of the roles of Chtf18 in mammals will broaden our knowledge of the underlying molecular aspects of gametogenesis and chromosomal segregation in mammals, and will provide insight into human infertility and reproductive disorders.
Selected publications and presentations
Berkowitz, K.M., Wang, P.J., Yang, F., Koenig, L.R., Jongens, T.A., and Kaestner, K.H.: Deletion of
Chtf18 Causes Premature Separation of Homologous Chromosomes during Meiosis in Male Mice, submitted.
Berkowitz, KM, Kaestner, KH, Jongens, TA: Germline Expression of Mammalian CTF18, an Evolutionarily Conserved Protein Required for Germ Cell Proliferation in the Fly and Sister Chromatid Cohesion in Yeast, Molecular Human Reproduction, Vol. 14(3): 143-150 (2008) (Cover).
Berkowitz, K.M., Hashmi, M.A., Yang, F., Wang, P. J., Jongens, T.A., Kaestner, K.H. CTF18 Plays
Important Roles in Mammalian Germ Cell Development and Embryonic Viability. The 56th Annual Meeting of the Society for Gynecologic Investigation, Glasgow, UK, March 17-21, 2009 (Oral presentation).
Berkowitz, K.M., Yang, F., Wang, P. J., Hashmi, M.A., Jongens, T.A., Kaestner, K.H. CTF18 Plays an
Important Role in Mammalian Gametogenesis and Fertility. Presented at the American Society for Reproductive Medicine 64th Annual Meeting, San Francisco, CA, November 8-12, 2008.
Berkowitz, K.M., Koenig, L.R., Yang, F., Wang, P. J., Jongens, T.A., Kaestner, K.H. CTF18: A New
Player in Mammalian Germ Cell Development. Presented at the Women’s Reproductive Health Research Scholars Symposium, Portland, OR, May 14-17, 2007 (Oral presentation).
Berkowitz, K.M., Koenig, L.R., Yang, F., Wang, P. J., Jongens, T.A., Kaestner, K. CTF18 Plays an Essential Role in Mammalian Gametogenesis. Presented at the 54th Annual Meeting of the Society for Gynecologic Investigation, Reno, Nevada, March 14-17, 2007 (Oral presentation). |