NCBI Summary:
The protein encoded by this gene is a helix-loop-helix (HLH) protein that can form heterodimers with members of the basic HLH family of transcription factors. The encoded protein has no DNA binding activity and therefore can inhibit the DNA binding and transcriptional activation ability of basic HLH proteins with which it interacts. This protein may play a role in cell growth, senescence, and differentiation. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
General function
Transcription factor
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Cellular localization
Nuclear
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Ovarian function
Follicle endowment, Initiation of primordial follicle growth
Comment
Single-cell RNA-Seq reveals a highly coordinated transcriptional program in mouse germ cells during primordial follicle formation. He Y et al. (2021) The assembly of primordial follicles in mammals represents one of the most critical processes in ovarian biology. It directly affects the number of oocytes available to a female throughout her reproductive life. Premature depletion of primordial follicles contributes to the ovarian pathology primary ovarian insufficiency (POI). To delineate the developmental trajectory and regulatory mechanisms of oocytes during the process, we performed RNA-seq on single germ cells from newborn (P0.5) ovaries. Three cell clusters were classified which corresponded to three cell states (germ cell cyst, cyst breakdown, and follicle) in the newborn ovary. By Monocle analysis, a uniform trajectory of oocyte development was built with a series of genes showed dynamic changes along the pseudo-timeline. Gene Ontology term enrichment revealed a significant decrease in meiosis-related genes and a dramatic increase in oocyte-specific genes which marked the transition from a germ cell to a functional oocyte. We then established a network of regulons by using single-cell regulatory network inference and clustering (SCENIC) algorithm and identified possible candidate transcription factors that may maintain transcription programs during follicle formation. Following functional studies further revealed the differential regulation of the identified regulon Id2 and its family member Id1, on the establishment of primordial follicle pool by using siRNA knockdown and genetic modified mouse models. In summary, our study systematically reconstructed molecular cascades in oocytes and identified a series of genes and molecular pathways in follicle formation and development.////////////////// 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
Growth Factors/ cytokines, BMP4
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tgfb
Ovarian localization
Cumulus, Granulosa, Theca, Luteal cells
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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.
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.
Follicle stages
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Role for Inhibitor of Differentiation/DNA Binding (Id) Proteins in Granulosa Cell Differentiation. Johnson AL et al. Recent studies in the hen ovary have linked the initiation of granulosa cell differentiation at follicle selection to the alleviation of inhibitory MAPK signaling. The present studies assessed a role for individual Id (inhibitor of differentiation) protein isoforms as modulators of key transcriptional events occurring within granulosa cells at or immediately subsequent to differentiation. Findings from freshly collected granulosa cells collected at different stages of follicle development demonstrated a negative association between expression levels for Id2 mRNA compared to levels of Id1, Id3 and Id4. Elevated levels of Id2 are related to a differentiating/differentiated phenotype, whereas elevated Id1, Id3 and Id4 are associated with an undifferentiated phenotype. This negative relationship extends to cell signal transduction, as factors that promote inhibitory MAPK signaling (transforming growth factor alpha and betacellulin) block expression of Id2 mRNA but increase levels of Id1, Id3 and Id4. Furthermore, over-expression of Gallus Id2 in cultured granulosa was found to significantly decrease levels of Id1, Id3 and Id4 mRNA, but facilitate FSHR mRNA expression and, importantly, initiate LHR mRNA expression plus LH-induced progesterone production. Finally, knock-down studies using siRNA specific for Id2 revealed reduced expression of FSHR and LHR mRNA, and attenuated FSH- and LH-induced levels of StAR and p450 cholesterol side chain cleavage enzyme mRNA plus progesterone production. Collectively, these data demonstrate that Id2 expression is both sufficient and necessary for increasing LHR expression and, as a result, promoting gonadotropin-induced differentiation in hen granulosa cells subsequent to follicle selection.