The overall goal of the project is understanding the roles of proto- oncogenes in gametogenesis and early development of mammalian embryos. The proposed research is focused on the mechanisms that regulate transcription of the c-mos gene, which plays a critical role in meiosis of vertebrate oocytes. Transcription of c-mos is subject to stringent tissue--specific regulation, leading to its specific expression in male and female germ cells. Such regulation of c-mos is needed not only to achieve appropriate c-mos expression in germ cells but also to prevent inappropriate expression in somatic cells, which can result in either cell death or neoplastic transformation. It is also noteworthy that c- mos expression is downregulated early in embryogenesis, which may be necessary to prevent arrest of embryonic cleavage divisions resulting from the action of Mos as a cytostatic factor. Transcription of c-mos in somatic cells is suppressed by a negative regulatory element (NRE) upstream of the c-mos promoter. In addition, recent studies have identified a candidate somatic cell repressor that binds to a functional element within the c-mos NRE. We now plan to isolate a cDNA clone of the repressor protein and to characterize its mechanism of action in suppressing transcription of c-mos, and possibly other germ cell-specific genes, in somatic cells. Expression of c-mos in oocytes, which is not affected by the NRE, requires only a minimal promoter, including an initiator (Inr) element. These findings suggest the hypothesis that c-mos transcription in oocytes results from a high level of basal transcription activity, which is then suppressed in two-cell embryos. This will be investigated by further studies of the activity of the c-mos Inr in directing transcription in oocytes and embryos, together with analysis of the expression and function of the c-mos repressor during embryonic development. The proposed studies have three specific aims: 1. Isolation and characterization of a cDNA clone for a somatic cell repressor of c-mos transcription. 2. Structure/function analysis and studies of the mechanism of c-mos repressor action. 3. Investigation of the regulation of c-mos transcription in oocytes and early embryos.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD026594-09
Application #
2883127
Study Section
Special Emphasis Panel (ZRG2-HED-2 (01))
Program Officer
Tasca, Richard J
Project Start
1998-03-01
Project End
2002-02-28
Budget Start
1999-03-01
Budget End
2002-02-28
Support Year
9
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Boston University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Boston
State
MA
Country
United States
Zip Code
02215
Gross, Vera S; Hess, Mailee; Cooper, Geoffrey M (2005) Mouse embryonic stem cells and preimplantation embryos require signaling through the phosphatidylinositol 3-kinase pathway to suppress apoptosis. Mol Reprod Dev 70:324-32
Zilz, Alexandra; Cooper, Geoffrey M (2004) A binding site for germ cell nuclear factor within c-mos regulatory sequences. Mol Reprod Dev 67:55-64
Gross, Vera S; Cooper, Geoffrey M (2002) Functional analysis of sperm from c-mos(-/-) mice. Mol Reprod Dev 62:519-24
Lin, H B; Jurk, M; Gulick, T et al. (1999) Identification of COUP-TF as a transcriptional repressor of the c-mos proto-oncogene. J Biol Chem 274:36796-800
Xu, W; Cooper, G M (1995) Identification of a candidate c-mos repressor that restricts transcription of germ cell-specific genes. Mol Cell Biol 15:5369-75
Gebauer, F; Xu, W; Cooper, G M et al. (1994) Translational control by cytoplasmic polyadenylation of c-mos mRNA is necessary for oocyte maturation in the mouse. EMBO J 13:5712-20
Yamauchi, N; Kiessling, A A; Cooper, G M (1994) The Ras/Raf signaling pathway is required for progression of mouse embryos through the two-cell stage. Mol Cell Biol 14:6655-62
Pal, S K; Torry, D; Serta, R et al. (1994) Expression and potential function of the c-mos proto-oncogene in human eggs. Fertil Steril 61:496-503
Pal, S K; Crowell, R; Kiessling, A A et al. (1993) Expression of proto-oncogenes in mouse eggs and preimplantation embryos. Mol Reprod Dev 35:8-15
Zinkel, S S; Pal, S K; Szeberenyi, J et al. (1992) Identification of a negative regulatory element that inhibits c-mos transcription in somatic cells. Mol Cell Biol 12:2029-36

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