Activin A Signaling Induces Smad2, but Not Smad3, Requiring Protein Kinase A Activity in Granulosa Cells from the Avian Ovary

Schmierer, Bernhard; Schuster, Michael; Shkumatava, Alena; Kuchler, Karl

doi:10.1074/jbc.m212425200

Cited by 24 publications

(25 citation statements)

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“…There is a significant increase in the theca content of activin A found within the most recently selected (9-mm-diameter) follicle [16], suggesting the potential for paracrine signaling at the time of follicle selection. Moreover, avian homologs to type I and type II TGF␤ and activin receptors as well as their associated cell signaling components (Smad2, 3, 4, and 7) have been identified [17, 18; GenBank accession AF230192], and several of these have been described within hen granulosa cells [19][20][21]. Such findings support the possibility of a paracrine and/or autocrine function for activin and TGF␤ within hen follicles.…”

Section: Introductionmentioning

confidence: 72%

“…Previously published data demonstrate that activin A treatment promotes Smad2 phosphorylation and nuclear translocation in hen granulosa cells from preovulatory follicles [21]. Additionally, both FSH and TGF␤ can upregulate levels of smad2 (but not smad3) mRNA expression [19,21].…”

Section: Introductionmentioning

confidence: 96%

“…Additionally, both FSH and TGF␤ can upregulate levels of smad2 (but not smad3) mRNA expression [19,21]. Combination treatment with FSH and activin A has been reported to stimulate or inhibit cell proliferation and to decrease LH-R mRNA expression in preovulatory follicle granulosa cells [22,23].…”

Section: Introductionmentioning

confidence: 97%

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Cellular Mechanisms and Modulation of Activin A- and Transforming Growth Factor β-Mediated Differentiation in Cultured Hen Granulosa Cells1

Johnson

Bridgham

Woods

2004

Biology of Reproduction

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Undifferentiated granulosa cells from prehierarchal (6- to 8-mm-diameter) hen follicles express very low to undetectable levels of LH receptor (LH-R) mRNA, P450 cholesterol side chain cleavage (P450scc) enzyme activity, and steroidogenic acute regulatory (StAR) protein, and produce negligible progesterone, in vitro, following an acute (3-h) challenge with either FSH or LH. It has previously been established that culturing such cells with FSH for 18-20 h induces LH-R, P450scc, and StAR expression, which enables the initiation of progesterone production. The present studies were conducted to characterize the ability of activin and transforming growth factor (TGF) beta, both alone and in combination with FSH, to promote hen granulosa cell differentiation, in vitro. A 20-h culture of prehierarchal follicle granulosa cells with activin A or transforming growth factor beta (TGFbeta)1 increased LH-R mRNA levels compared with control cultured cells. Activin A and TGFbeta1 also promoted FSH-receptor (FSH-R) mRNA expression when combined with FSH treatment. Neither activin A nor TGFbeta1 alone stimulated progesterone production after 20 h culture. However, preculture with either factor for 20 h (to induce gonadotropin receptor mRNA expression) followed by a 3-h challenge with FSH or LH potentiated StAR expression and progesterone production compared with cells challenged with gonadotropin in the absence of activin A or TGFbeta1 preculture. Significantly, activation of the mitogen-activated protein (MAP) kinase pathway with transforming growth factor alpha (TGFalpha) (monitored by Erk phosphorylation) blocked TGFbeta1-induced LH-R expression, and this effect was associated with the inhibition of Smad2 phosphorylation. We conclude that a primary differentiation-inducing action of activin A and TGFbeta1 on hen granulosa cells from prehierarchal follicles is directed toward LH-R expression. Enhanced LH-R levels subsequently sensitize granulosa cells to LH, which in turn promotes StAR plus P450scc expression and subsequently an increase in P4 production. Significantly, the finding that TGFbeta signaling is negatively regulated by MAP kinase signaling is proposed to represent a mechanism that prevents premature differentiation of granulosa cells.

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Section: Introductionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 96%

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Cellular Mechanisms and Modulation of Activin A- and Transforming Growth Factor β-Mediated Differentiation in Cultured Hen Granulosa Cells1

Johnson

Bridgham

Woods

2004

Biology of Reproduction

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“…In vivo, Smad2 and Smad3 show differential expression in rat estrous cycle, Smad2 expression, but not Smad3, is observed in luteal cells, the relative effectiveness of the growth factors suggests a functional preference of Smad2 for activation by activin and Smad3 for activation by TGFb in GCs (Xu et al 2002). Schmierer et al (2003) reported that activin A signaling induces Smad2 but not Smad3 in GCs from the avian ovary. Consistent with differential expression of Smad2 and Smad3 in the ovary, there also seems to be functional differences in their regulation of key events related to follicle development.…”

Section: Discussionmentioning

confidence: 99%

SMAD3 regulates the diverse functions of rat granulosa cells relating to the FSHR/PKA signaling pathway

Jin

Liu

et al. 2013

Reproduction

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The function of Smad3, a downstream signaling protein of the transforming growth factor b (TGFb) pathway, in ovarian follicle development remains to be elucidated. The effects of Smad3 on ovarian granulosa cells (GCs) in rat were studied. Female rats (21 days of age Sprague-Dawley) received i.p. injections of pregnant mare serum gonadotropin, and GCs were harvested for primary culture 48 h later. These cells were engineered to overexpress or knockdown Smad3, which were validated by immunohistochemistry and western blot. The expression of proliferating cell nuclear antigen (PCNA), cyclin D2, TGFb receptor II (TGFbRII), protein kinase A (PKA), and FSH receptor (FSHR) was also detected by western blotting. Cell cycle and apoptosis of GCs were assayed by flow cytometry. The level of estrogen secreted by GCs was detected by ELISA. Smad3 overexpression promoted estrogen production and proliferation while inhibiting apoptosis of GCs. Reduction in Smad3 by RNAi resulted in reduced estrogen production and proliferation and increased apoptosis of GCs. Manipulation of Smad3 expression also resulted in changes in FSHR and PKA expression, suggesting that the effects of Smad3 on follicle development are related to FSHR-mediated cAMP signaling.

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“…Activin receptors are expressed by theca cells, granulosa cells, and the oocyte, and binding of activin A to its receptor on these cells enhances preantral follicle growth and granulosa cell proliferation (13,14). Activin A treatment of avian granulosa cells not only leads to phosphorylation and nuclear translocation of Smad 2 and 3 but even increased Smad2 expression (15). Smad3 expression was found to be unchanged in that study, and Smad4 was not investigated.…”

mentioning

confidence: 93%

Bridge-1 is expressed in human granulosa cells and is involved in the activin A signaling cascade

Banz¹,

Münchow²,

Diedrich³

2010

Fertility and Sterility

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Activin A Signaling Induces Smad2, but Not Smad3, Requiring Protein Kinase A Activity in Granulosa Cells from the Avian Ovary

Cited by 24 publications

References 50 publications

Cellular Mechanisms and Modulation of Activin A- and Transforming Growth Factor β-Mediated Differentiation in Cultured Hen Granulosa Cells1

Cellular Mechanisms and Modulation of Activin A- and Transforming Growth Factor β-Mediated Differentiation in Cultured Hen Granulosa Cells1

SMAD3 regulates the diverse functions of rat granulosa cells relating to the FSHR/PKA signaling pathway

Bridge-1 is expressed in human granulosa cells and is involved in the activin A signaling cascade

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