In the ovary, the Rhox library is the lender and some genes are the borrowers. Dias JA 2013 et al.
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General function
Nucleic acid binding, DNA binding, Transcription factor
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Cellular localization
Nuclear
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Ovarian function
Antral follicle growth
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Regulated Expression of Rhox8 in the Mouse Ovary: Evidence for the Role of Progesterone and RHOX5 in Granulosa Cells. Brown RM et al. The gonadotropin surge is the essential trigger to stimulate ovulation and luteinization of ovarian follicles. While the hormone signals from the brain that initiate ovulation are known, the specific targets which regulate this process are not well known. In this report, we assess the suitability of the Rhox homeobox gene cluster to serve as master regulators of folliculogenesis. In superovulated (eCG/hCG) mice, the Rhox genes exhibited four distinct windows of peak expression, suggesting that these genes may regulate specific events during the ovulatory cycle. Like many members of the cluster, Rhox8 mRNA and protein was induced by FSH/eCG in granulosa cells. However, Rhox8 displayed unique peak expression at 8 h post-hCG, implying it might be the lone member of the cluster regulated by progesterone. Subsequent promoter analysis in granulosa cells revealed relevant homeobox binding and progesterone response elements within Rhox8's 5'-flanking region. In superovulated mice, PGR is recruited to the Rhox8 promoter, as assessed by ChIP. In Rhox5-null mice, Rhox8 mRNA is reduced at 2 h and 4 h post hCG, but recovered once the follicles passed the antral stage of development. Conversely, in progesterone receptor knockout mice (PRKO), Rhox8 exhibited normal stimulation by eCG, but failed to reach its peak mRNA level at 8 h post-hCG found in WT mice. This suggests a model in which Rhox8 transcription is dependent upon RHOX5 during early folliculogenesis and upon progesterone during the periovulatory window when RHOX5 normally wanes. In support of this model, transfection of RHOX5 and PGR expression plasmids stimulated, whereas dominant negative and mutant constructs inhibited, Rhox8 promoter activity.
Expression regulated by
LH
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Ovarian localization
Granulosa
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Regulation of the Rhox5 Homeobox Gene in Primary Granulosa Cells: Preovulatory Expression and Dependence on SP1/SP3 and GABP Maclean JA 2nd, et al .
Homeobox genes encode transcription factors that regulate embryonic development and postnatal events. Rhox5 (previously called Pem), the founding member of a homeobox gene cluster that we recently identified on the X chromosome, is selectively expressed in granulosa cells in the ovary and other somatic-cell types in other reproductive organs. In this report, we investigate its regulation in granulosa cells in the rat ovary. We found that Rhox5 expression in the ovary is governed by the Rhox5 distal promoter and is expressed at least as early as Day 5 postpartum. Rhox5 mRNA levels are regulated during the ovarian cycle, peaking before ovulation. Deletion analysis revealed a 25-nt element essential for distal promoter transcription in primary granulosa cells. This distal promoter element contains two ETS and one SP1 transcription-factor family binding sites that mutagenesis analysis indicated were essential for high-level transcription. This element was both necessary and sufficient for transcription, because it activated transcription when placed upstream of a heterologous minimal promoter. Cold competition and electrophoretic mobility shift assay studies demonstrated that SP1, SP3, and the ETS family transcription factor GABP bound this element. Dominant-negative forms of GABP and SP3 repressed distal promoter expression in primary rat granulosa, showing that these factors are crucial for Rhox5 expression. Cotransfection of dominant-negative mutants indicated that Rhox5 expression in granulosa cells is regulated by the c-Jun N-terminal protein kinase (JNK, MAPK8) and RAS pathways, which are known to be upstream of ETS family transcription factors. The discovery that Rhox5 expression in granulosa cells is regulated by MAPK pathways and ETS and SP1 family members provides an opportunity to understand how these regulatory pathways and factors collaborate to regulate gene expression during the ovarian cycle.