Human homolog of the Drosophila gene 'mothers against
decapentaplegic' (Mad) and the C. elegans gene Sma, are components of signal transduction pathways. The
human gene, symbolized MADR1 by the authors, encodes a 465-amino acid polypeptide.
General function
Comment
Cellular localization
Cytoplasmic, Nuclear
Comment
Ovarian function
Follicle development
Comment
Anti-müllerian hormone regulation by the bone morphogenetic proteins in the sheep ovary: deciphering a direct regulatory pathway. Estienne A et al. (2014) In the ovary, anti-Müllerian hormone (AMH) is produced by the granulosa cells of growing follicles and can modulate the recruitment of primordial follicles and the FSH-dependent development of follicles. However, the regulation of its production remains poorly understood. Recently, a stimulating effect of the bone morphogenetic proteins (BMPs) on AMH production by granulosa cells has been shown in vitro, but the molecular mechanisms implicated in this regulation and its physiological importance in ovarian function have not yet been established. In the hyperprolific Booroola ewes carrying the FecB(B) partial loss-of-function mutation in the fecundity gene encoding the FecB/BMP receptor, type 1B, the granulosa cells of antral follicles expressed and secreted low AMH amounts, resulting in low AMH concentrations in blood, despite high numbers of AMH-secreting follicles in ovaries. The presence of the FecB(B) mutation impaired the granulosa cell response to the stimulating action of BMP4 on AMH production, indicating a crucial role of the BMP receptor, type 1B in AMH regulation. In ovine granulosa cells, BMP4 enhanced the transcriptional activity of the human AMH promoter, and this action depended on the presence of SMAD1, acting on a promoter sequence located between -423 and -202 bp upstream of the AMH transcription start site. SMAD1 and SF1 acted in concert to mediate BMP4 action on the AMH promoter. Among the 2 SF1 binding sites present on the AMH promoter, the most proximal site, located at -92 bp upstream of the AMH transcription start site, was found to be critical for ensuring the response of the AMH promoter to BMP4. In conclusion, AMH could mediate the actions of BMPs in regulating follicular development and contributing to the determination of ovulation numbers. A molecular model of regulation of the AMH promoter transactivation by BMP signaling is proposed.//////////////////
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, AMH
Comment
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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Ovarian localization
Oocyte, Granulosa, Theca
Comment
Follicle stages
Primary, Secondary, Antral
Comment
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment: Mouse embryos lacking Smad1 signals display defects in extra-embryonic tissues and germ cell formation Tremblay KD, et al .
The Smad proteins are important intracellular mediators of the transforming growth factor beta (TGFbeta) family of secreted growth factors. Smad1 is an effector of signals provided by the bone morphogenetic protein (BMP) sub-group of TGFbeta molecules. To understand the role of Smad1 in mouse development, we have generated a Smad1 loss-of-function allele using homologous recombination in ES cells. Smad1-/- embryos die by 10.5 dpc because they fail to connect to the placenta. Mutant embryos are first recognizable by 7.0 dpc, owing to a characteristic localized outpocketing of the visceral endoderm at the posterior embryonic/extra-embryonic junction, accompanied by a dramatic twisting of the epiblast and nascent mesoderm. Chimera analysis reveals that these two defects are attributable to a requirement for Smad1 in the extra-embryonic tissues. By 7.5 dpc, Smad1-deficient embryos show a marked impairment in allantois formation. By contrast, the chorion overproliferates, is erratically folded within the extra-embryonic space and is impeded in proximal migration. BMP signals are known to be essential for the specification and proliferation of primordial germ cells. We find a drastic reduction of primordial germ cells in Smad1-deficient embryos, suggesting an essential role for Smad1-dependent signals in primordial germ cell specification. Surprisingly, despite the key involvement of BMP signaling in tissues of the embryo proper, Smad1-deficient embryos develop remarkably normally. An examination of the expression domains of Smad1, Smad5 and Smad8 in early mouse embryos show that, while Smad1 is uniquely expressed in the visceral endoderm at 6.5 dpc, in other tissues Smad1 is co-expressed with Smad5 and/or Smad8. Collectively, these data have uncovered a unique function for Smad1 signaling in coordinating the growth of extra-embryonic structures necessary to support development within the uterine environment.
Species: mouse
Mutation name: None
type: null mutation fertility: None Comment: Smad1-Smad5 Ovarian Conditional Knockout Mice Develop a Disease Profile Similar to the Juvenile Form of Human Granulosa Cell Tumors. Middlebrook BS et al. Granulosa cell tumors (GCTs) of the ovary are rare sex cord stromal tumors. Although generally indolent, GCTs recur, and if not diagnosed and treated in early stages, survival rates are significantly shortened. Very little is known regarding GCT etiology. Because of the low incidence of cases and lack of standard diagnostics, mouse models for granulosa cell tumors are a valuable tool for studying GCTs and provide models for developing diagnostic and treatment strategies. We recently developed a novel mouse model of metastatic granulosa cell tumors by genetic deletion of the bone morphogenetic protein signaling transcription factors (SMADs) in granulosa cells of the ovary. Histological and serum hormone analyses reveal that this mouse model most closely resembles the juvenile form of GCT. We further analyzed samples of human juvenile GCT (JGCT) for expression of anti-M?an hormone and activation of two major signaling pathways: TGFbeta/SMAD2/3 and wingless-related mouse mammary tumor virus integration site (Wnt)/beta-catenin. The TGFbeta family is active in mouse Smad1-Smad5 double knockout tumors, and here we show that this pathway, but not the beta-catenin pathway, is activated in samples of human JGCT. These data suggest that the SMAD family, possibly through disruption of SMAD1/5 or activation of SMAD2/3 may contribute to the pathogenesis of JGCT in humans.