Human homolog of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the
C. elegans gene Sma, are components of TGF-beta/activin/BMP/GDF signal transduction pathways.
NCBI Summary:
The protein encoded by this gene is a nuclear protein that binds the E3 ubiquitin ligase SMURF2. Upon binding, this complex translocates to the cytoplasm, where it interacts with TGF-beta receptor type-1 (TGFBR1), leading to the degradation of both the encoded protein and TGFBR1. Expression of this gene is induced by TGFBR1. Variations in this gene are a cause of susceptibility to colorectal cancer type 3 (CRCS3). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]
General function
Comment
Cellular localization
Cytoplasmic, Nuclear
Comment
Ovarian function
Follicle development, Follicle atresia
Comment
Ann E. Drummond, et al 2002 reported the expression and Localization of Activin Receptors, Smads, and ?lycan to the Postnatal Rat Ovary.
Despite understanding the molecular basis of activin/TGF?and bone morphogenetic protein (BMP) signaling, this study is
the first to characterize multiple, sequential elements of these pathways in the ovary concurrently. The expression of
activin/BMP receptor, Smad, and ?lycan mRNAs by postnatal rat ovaries were investigated by real-time PCR.
Activin/BMP receptors (ActRIA, ActRIB, ActRIIA, and ActRIIB), ?lycan, and Smad 1-8 mRNAs were expressed by the
ovary. Activin receptor and Smad 1, 2, 4, 5, and 7 mRNAs declined up to 4-fold between postnatal d 4-8, coinciding with
secondary follicle formation. The emergence of antral follicles (postnatal d 12) saw ActRIA, ActRIIB, and Smad 2 mRNA
expression return to d 4 levels, whereas ActRIB, ActRIIA, and Smads 1, 4, 5, and 7 remained at lower levels. ?lycan
mRNA levels increased 2-fold between d 8 and 12, suggesting expression by the developing theca. Smad 3, 6, and 8 mRNAs
were unchanged. Activin receptor and Smad proteins were present in oocytes at all stages of follicular development;
granulosa cells of primary-antral follicles, and theca cells.
Expression regulated by
Growth Factors/ cytokines, BMP, mir92a, mir21
Comment
miR-21 is involved in norepinephrine-mediated rat granulosa cell apoptosis by targeting SMAD7. Zhang L et al. (2017) Substantive evidence has indicated that the sympathetic innervation contributes to the regulation and development of ovarian functions. Norepinephrine (NE) is one of the major neurotransmitters contained in the extrinsic ovarian sympathetic nerves and is thought to be a potent moderator of ovarian functions such as steroidogenesis and granulosa cell proliferation or apoptosis. However, the mechanisms of NE regulation of granulosa cell apoptosis in the rat ovary are rare. Real-time PCR and Western blot results show that NE regulates the expression of miR-21 in primary granulosa cells in a dose-dependent manner. Additionally, we found that miR-21 is involved in NE-mediated rat granulosa cells apoptosis and blocks granulosa cell apoptosis by targeting Smad7, a transforming growth factor-beta-inducible mediator of apoptosis in granulosa cells. In primary granulosa cells, a combined treatment of NE and TGF-β increased apoptosis and decreased miR-21 expression, but increased SMAD7 protein levels. We also demonstrated that NE regulates miR-21 by coupling to α1A-adrenergic receptor (α1A-AR). This is the first demonstration that NE controls the reproductive functions by modulating the expression of miR-21 and promoting TGF-β-induced granulosa cell apoptosis. Such NE-mediated effects could be potentially used for regulating the reproductive processes and for treating reproductive disorders.//////////////////
MiR-92a inhibits porcine ovarian granulosa cell apoptosis by targeting Smad7 gene. Liu J et al. (2015) Smad7 has a key role in apoptosis of mammalian ovarian granulosa cells (GCs), as it antagonizes and fine-tunes transforming growth factor β (TGFβ) signaling. This study demonstrates that miR-92a regulates GC apoptosis in pig ovaries by targeting Smad7 directly. The expression level of miR-92a was down-regulated in atretic porcine follicles, whereas miR-92a expression led to inhibition of GC apoptosis. The Smad7 gene was identified as a direct target of miR-92a using a dual-luciferase reporter assay. Transfection of GCs with miR-92a mimics decreased Smad7 mRNA and protein levels, whereas expression of an miR-92a inhibitor in GCs had the opposite effect. In addition, knockdown of Smad7 prevented GC apoptosis in cells that expressed the miR-92a inhibitor.//////////////////
Smad7 is a transforming growth factor-beta-inducible mediator of?apoptosis in granulosa cells. Quezada M et al. To determine the functional role of Smad7 in granulosa cells.Granulosa cell culture and molecular biological techniques were used to investigate regulation and function of Smad7.
SETTING:
Research laboratory.
ANIMAL(S):
C57bl/j hybrid mouse.
INTERVENTION(S):
Primary mouse granulosa cells were isolated and grown in culture for all messenger RNA expression experiments. Smad7 promoter constructs were evaluated with a luciferase reporter system in SIGC cells to determine sites activating Smad7 expression.
MAIN OUTCOME MEASURE(S):
Overexpression (Smad7 complementary DNA) and downregulation (Smad7 small interfering RNA) of Smad7 in primary mouse granulosa cells were used to evaluate the functional role of Smad7 in granulosa cells.
RESULT(S):
Smad7 expression was upregulated by treatment with transforming growth factor-β (TGF-β) but not activin or activation of the cyclic adenosine monophosphate pathway. The promoter of Smad7 was activated by TGF-β. Truncation of the promoter or mutation of the Smad response element at -141 eliminated TGF-β activation of the promoter. Smad3 was not specifically required for TGF-β-stimulated expression of Smad7, though activation of the TGFBR1 receptor was. When Smad7 was overexpressed in granulosa cells, apoptosis was markedly increased. When Smad7 expression was reduced with small interfering RNA, then the TGF-β-induced apoptosis was blocked.
CONCLUSION(S):
Smad7 mediates apoptosis induced by TGF-β in mouse granulosa cells, suggesting that dysregulation of Smad7 could impair folliculogenesis.
Ovarian localization
Oocyte, Granulosa, Theca
Comment
SMAD7 Antagonizes Key TGF Superfamily Signaling in Mouse Granulosa Cells in vitro. Gao Y et al. Transforming growth factor (TGF) superfamily signaling is essential for female reproduction. Dysregulation of the TGF signaling pathway can cause reproductive diseases. SMAD [SMA and MAD (Mothers against decapentaplegic)] proteins are downstream signaling transducers of the TGF superfamily. SMAD7 is an inhibitory SMAD that regulates TGF signaling in vitro. However, the function of SMAD7 in the ovary remains poorly defined. To determine the signaling preference and potential role of SMAD7 in the ovary, we herein examined the expression, regulation, and function of SMAD7 in mouse granulosa cells. We showed that SMAD7 was expressed in granulosa cells and subject to the regulation by intraovarian growth factors from the TGF superfamily. TGF1, bone morphogenetic protein 4 (BMP4), and oocyte-derived growth differentiation factor 9 (GDF9) were capable of inducing Smad7 expression, suggesting a modulatory role of SMAD7 in a negative feedback loop. Using a small interfering RNA (siRNA) approach, we further demonstrated that SMAD7 was a negative regulator of TGF1. Moreover, we revealed a link between SMAD7 and GDF9-mediated oocyte paracrine signaling, an essential component of oocyte-granulosa cell communication and folliculogenesis. Collectively, our results suggest that SMAD7 may function during follicular development via preferentially antagonizing and/or fine-tuning essential TGF superfamily signaling, which is involved in the regulation of oocyte-somatic cell interaction and granulosa cell function.