NCBI Summary:
This gene encodes a mitogen-activated kinase which localizes to the nucleus. The gene maps to the major histocompatability complex (MHC) class II region on chromosome 6p21.3 but sequence comparison suggests that the protein is not involved in the immune response. Homology to the Drosophila gene female sterile homeotic suggests that this human gene may be part of a signal transduction pathway involved in growth control.
General function
Cell proliferation
Comment
Cellular localization
Cytoplasmic, Nuclear
Comment
Ovarian function
Follicle development
Comment
[P3-25] The Bromodomain-Containing Gene, Fsrg1/Brd2, Is Expressed in Distinct Patterns during Ovarian Folliculogenesis Independent from FSH or GDF9 Action.
Rhonda K Trousdale, Debra J Wolgemuth Genet and Devel, Ob and Gyn, Inst of Hum Nutrit, Columbia Univ, New York City, NY
Fsrg1 is a member of a family of genes most homologous to the Drosophila gene female sterile homeotic (fsh), containing two tandem bromodomains and an ET domain. Most proteins containing a bromodomain have a role in regulating transcription as one of their potential cellular functions. Studies of the fsh-subgroup have advocated a role for Fsrg1 in both mitotic and meiotic cell cycle regulation as well.
We previously observed high levels of Fsrg1 expression in several hormonally responsive tissues, including the ovary. To evaluate potential changes in ovarian expression throughout folliculogenesis, in situ hybridization analysis was carried out on ovaries (n=14) from randomly cycling adult mice 4-20 weeks of age. Fsrg1 transcripts were identified in all major cell types: granulosa cells, thecal cells, stromal cells, oocytes and corpora lutea. As the oocyte develops, three distinct patterns of Fsrg1 localization emerge: a diffuse distribution in both the cytoplasm and nucleus, followed by intense nuclear localization, then exclusion of Fsrg1 transcripts from the nucleus. The transition from intense nuclear localization to nuclear exclusion correlates with oocyte maturation and meiotic competence, as determined by nuclear chromatin patterns.
To determine if disruption of normal folliculogenesis would affect Fsrg1 expression, we evaluated Fsrg1 transcript localization in FSH-null (n=2) and Gdf9-null (n=2) mice. Folliculogenesis in FSH-null mice is blocked at the pre-antral phase and in Gdf9-null mice at the one-cell layer stage. In both models Fsrg1 was identified in all major cell types. Oocyte sub-localization patterns were similar and the transition from intense nuclear expression to exclusion also correlated with oocyte maturity. Thus, Fsrg1 expression was independent of FSH or Gdf9 function.
The highest level of Fsrg1 expression for all models studied was seen in granulosa cells of growing follicles, stage 3a-8, suggesting a role for Fsrg1 in the mitotic cell cycle. Fsrg1 expression decreased in the early, luteinized corpus luteum, when granulosa cells cease to proliferate. However, Fsrg1 expression increased in the de-lutenized, degenerating corpus luteum suggesting a role for Fsrg1 in apoptosis. These data are consistent with a role for Fsrg1 in cell cycle regulation.
Bromodomain containing 2 (Brd2) is expressed in distinct patterns during ovarian folliculogenesis independent of FSH or GDF9 action.
Trousdale RK, et al previously observed high levels of Brd2 (also known as female sterile homeotic related gene-1, Fsrg1) expression in several hormonally responsive tissues, including the ovary. Here, we report distinct localization patterns of Brd2 transcripts throughout ovarian folliculogenesis in normal mice as well as in two strains of mice with aberrant folliculogenesis: mice with mutated growth differentiation factor 9 (Gdf9) and follicle stimulating hormone beta (Fshb) genes. The highest level of expression was seen in granulosa cells of growing follicles. Within the oocyte, three patterns of Brd2 RNA localization were observed: diffuse distribution in both the cytoplasm and nucleus, then intense nuclear expression, followed by an absence of Brd2 transcripts from the nucleus. The transition from intense nuclear localization to nuclear exclusion was found to correlate with oocyte maturation and meiotic competence, as determined by nuclear chromatin patterns. These same expression patterns were also seen in oocytes from Gdf9(-/-) and Fshb(-/-) mice. Thus, Brd2 expression appears to correlate with stages of oocyte maturation, independent of FSH or GDF9 action and the subsequent disruption in normal follicle development in these models. The distinct patterns of Brd2 localization within the adult ovary supports a role for Brd2 in mitotic and possibly meiotic cell cycle regulation.