NCBI Summary:
The protein encoded by this gene is a helix-loop-helix (HLH) protein that can form heterodimers with other HLH proteins. However, the encoded protein lacks a basic DNA-binding domain and therefore inhibits the DNA binding of any HLH protein with which it interacts. [provided by RefSeq, Aug 2011]
General function
Nucleic acid binding, DNA binding, Transcription factor
Comment
Cellular localization
Nuclear
Comment
Ovarian function
Luteinization, Oogenesis, Oocyte maturation
Comment
Expression and localization of Inhibitor of Differentiation (ID) proteins during tissue and vascular remodelling in the human corpus luteum. Nio-Kobayashi J et al. Members of the transforming growth factor-?(TGF-? superfamily are likely to have major roles the regulation of tissue and vascular remodelling in the corpus luteum. There are four Inhibitor of Differentiation (ID1-4) genes that are regulated by members of the TGF-?superfamily and are involved in the transcriptional regulation of cell growth and differentiation. We studied their expression, localisation and regulation in dated human corpora lutea from across the luteal phase (n=22) and after human chorionic gonadotrophin (hCG) administration in vivo (n=5), and in luteinised granulosa cells (LGCs), using immunohistochemistry and quantitative RT-PCR. ID1-4 can be localised to multiple cell types in the corpus luteum across the luteal phase. Endothelial cell ID3 (P<0.05) and ID4 (P<0.05) immunostaining intensities peak at the time of angiogenesis but overall ID1 (P<0.05) and ID3 (P<0.05) expression peaks at the time of luteolysis and luteal ID3 expression is inhibited by hCG in vivo (P<0.01). In LGC cultures in vitro, hCG had no effect on ID1, down-regulated ID3 (P<0.001), and up-regulated ID2 (P<0.001) and ID4 (P<0.01). Bone morphogenic proteins (BMPs) had no effect on ID4 expression but up-regulated ID1 (P<0.01-P<0.005). BMP up-regulation of ID2 (P<0.05) was additive to the hCG upregulation of ID2 expression (P<0.001), while BMP cancelled out the down regulative effect of hCG on ID3 regulation. As well as documenting regulation patterns specific for ID1, ID2, ID3 and ID4, we have shown that IDs are located and differentially regulated in the human corpus luteum, suggesting a role in the transcriptional regulation of luteal cells during tissue and vascular remodelling.
Expression regulated by
FSH, Growth Factors/ cytokines, BMP4, AMH
Comment
ID3 mediates the TGF-β1-induced suppression of matrix metalloproteinase-1 in human granulosa cells. Li H et al. (2019) In the mammalian ovary, matrix metalloproteinase-1 (MMP1) is expressed in growing ovarian follicles, and MMP1-mediated extracellular matrix (ECM) remodeling plays a functional role in regulating the formation of corpus luteum. Transforming growth factor-β1 (TGF-β1) is an intraovarian growth factor that acts as a negative regulator of luteinization and progesterone production in human granulosa-lutein (hGL) cells. At present, whether TGF-β1 regulates the expression of MMP1 and thus affects ECM remodeling during corpus luteum formation remains largely unknown. The aim of this study was to investigate the effects of TGF-β1 and the molecular mechanisms by which it regulates the expression of MMP1 in immortalized human granulosa cells lines (SVOG) and primary hGL cells (obtained from consenting patients undergoing IVF treatment). We used inhibition approaches including a competitive antagonist for endogenous TGF-β type II receptor, pharmacological inhibitors (SB431542 and dorsomorphin) and specific small interfering RNA-targeted knockdown of ALK5 type I receptor and SMAD4 to demonstrate that TGF-β1 down-regulates the expression and production of MMP1 via a TβRII/ALK5-mediated SMAD-dependent signaling pathway in hGL cells. Additionally, our results show that the suppressive effect of TGF-β1 on the expression of MMP1 is mediated by a transcription factor, the inhibitor of differentiation 3 (ID3) protein. Our findings provide insights into the molecular interactions and mechanisms of TGF-β1 and ID3 during the regulation of MMP1 in hGL cells. This article is protected by copyright. All rights reserved.//////////////////
Anti-Mllerian Hormone Recruits BMPR-IA in Immature Granulosa Cells. Sdes L 2013 et al.
Anti-Mllerian hormone (AMH) is a member of the TGF- superfamily secreted by the gonads of both sexes. This hormone is primarily known for its role in the regression of the Mllerian ducts in male fetuses. In females, AMH is expressed in granulosa cells of developing follicles. Like other members of the TGF- superfamily, AMH transduces its signal through two transmembrane serine/threonine kinase receptors including a well characterized type II receptor, AMHR-II. The complete signalling pathway of AMH involving Smads proteins and the type I receptor is well known in the Mllerian duct and in Sertoli and Leydig cells but not in granulosa cells. In addition, few AMH target genes have been identified in these cells. Finally, while several co-receptors have been reported for members of the TGF- superfamily, none have been described for AMH. Here, we have shown that none of the Bone Morphogenetic Proteins (BMPs) co-receptors, Repulsive guidance molecules (RGMs), were essential for AMH signalling. We also demonstrated that the main Smad proteins used by AMH in granulosa cells were Smad 1 and Smad 5. Like for the other AMH target cells, the most important type I receptor for AMH in these cells was BMPR-IA. Finally, we have identified a new AMH target gene, Id3, which could be involved in the effects of AMH on the differentiation of granulosa cells and its other target cells.
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Identification of genes targeted by FSH and oocytes in porcine granulosa cells. Verbraak EJ et al. In the mammalian ovarian follicle maturing oocytes are nurtured and supported by surrounding somatic cells, the mural granulosa cells and the cumulus cells. These cells are regulated by follicle-stimulating hormone (FSH), originating from the pituitary, and paracrine factors derived from the oocyte. To gain insight into the mechanisms involved in the regulation of granulosa cell function, this study aimed to identify genes in mural granulosa cells that are regulated by FSH and oocyte secreted factors using the pig as a model organism. Mural granulosa cells were collected from 3-6 mm follicles from sow ovaries and cultured in serum free medium in the presence or absence of FSH and/or isolated cumulus oocyte complexes (COCs). FSH significantly increased both the metabolic activity and progesterone production of granulosa cells, while the presence of COCs reversed these FSH effects. Expression levels of mRNA in the absence/presence of FSH and COCs were analyzed on porcine specific microarrays representing 11,300 genes. Both previously identified and novel FSH target genes as well as some oocyte affected genes were found. Expression of inhibitor of DNA binding protein 2 and 3, ID2 and ID3, was decreased by FSH but increased by COCs, as validated by quantitative PCR. These proteins function as dominant negative basic helix loop helix (bHLH) transcription factors and since all regulated genes contain the consensus E-box sequence that can bind bHLH factors, our data suggest that FSH and COCs may regulate granulosa cell function by tuning the activity of bHLH factors, through ID2 and ID3.
Inhibitor of Differentiation (Id) Genes Are Expressed in the Steroidogenic Cells of the Ovine Ovary and Are Differentially Regulated by Members of the Transforming Growth Factor-{beta} Family. Hogg K et al. Inhibitor of differentiation (Id) proteins act during embryogenesis and development to repress gene transcription required for lineage commitment, while promoting cell growth. Growth factors belonging to the TGFbeta superfamily of signaling molecules, notably the bone morphogenetic proteins (BMPs) and activin, can regulate Id expression in these tissues. Id expression and function in adult physiology is less well determined, and we hypothesized a role for Id proteins in the adult mammalian ovary. Immunohistochemistry for Id1, Id2, Id3, and Id4 in the sheep ovary revealed consistent expression in granulosa and thecal cells of ovarian follicles throughout development. In atretic follicles, Id proteins were selectively down-regulated in thecal cells (P < 0.0001). Additionally, Id1 was universally up-regulated in the cumulus cells adjacent to the oocyte. Immunohistochemistry for phospho (p)-smad 1/5/8 signaling components (stimulated by BMPs) showed a punctate pattern of expression whereas p-smad 2/3 (stimulated by activin) was ubiquitously expressed in follicles. Neither pathway, however, displayed differential staining in line with Id1 cumulus-specific expression, suggesting a more complex relationship between Id1 expression and TGFbeta signaling in these cells. Nevertheless, in vitro, stimulation of ovine granulosa cells with BMP6 or activin A led to a respective increase and decrease in Id1 (P < 0.0001), Id2 (P < 0.0001), Id3 (P < 0.0001), and Id4 (P < 0.05) transcripts, and Id1 gene expression was further manipulated by the oocyte-secreted factors BMP15 and growth differentiation factor 9 (P < 0.001). These data confirm that TGFbeta signaling can regulate Id gene expression in the sheep ovarian follicle and suggest a functional role for the Id family in the mammalian ovary.
Ovarian localization
Granulosa, Theca, Luteal cells
Comment
Shepherd TG, et al 2003 reported the identification of a putative autocrine bone morphogenetic protein-signaling pathway in human ovarian surface epithelium and ovarian cancer cells.
Bone morphogenetic proteins (BMPs) are members of the TGFbeta superfamily of cytokines that are involved in development, differentiation, and disease. In an analysis of normal ovarian surface epithelium (OSE) and ovarian cancer (OC) cells, the authors observed BMP4 mRNA expression and found that primary OC cells produce mature BMP4. In addition, each member of the downstream signaling pathway was expressed in primary OSE and OC cells. Smad1 was phosphorylated and underwent nuclear translocation in normal OSE and OC cells upon treatment with BMP4. Interestingly, the BMP target genes ID1 and ID3 were up-regulated 10- to 15-fold in primary OC cells, compared with a 2- to 3-fold increase in normal OSE. The growth of several primary OC cells was relatively unaltered by BMP4 treatment; however, long-term BMP4 treatment of primary OC cells resulted in decreased cell density as well as increased cell spreading and adherence. These data demonstrate the existence and putative function of BMP signaling in normal OSE and OC cells, and thus the continued examination of BMP4 signaling in the regulation of these two processes will be critical to further our current understanding of the role of BMP biology in OC pathogenesis.