Non-canonical WNT5A is a potential regulator of granulosa cell function in cattle

Abedini, Atefeh; Zamberlam, Gustavo; Boerboom, Derek; Price, Christopher A.

doi:10.1016/j.mce.2015.01.017

Cited by 25 publications

(14 citation statements)

References 59 publications

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“…Our inability to detect activation of noncanonical signaling by WNT5a in murine GCs was unexpected, particularly considering that we have recently reported that WNT5a signals via a RAC1/JNK/JUN pathway in cultured bovine GCs (32). Although the basis for this discrepancy remains unknown, the culture systems used differed between the 2 studies.…”

Section: Discussionmentioning

confidence: 89%

“…Wnt5a and Wnt11 are expressed in mouse GCs (29), and Wnt5a transcripts have been detected in human luteinized GCs and cumulus cells (30, 31). We have recently identified Wnt5a as a gene whose expression is down‐regulated by FSH in a bovine primary GC culture model (32). We found that exogenous WNT5a suppressed FSH‐stimulated estradiol (E2) and P4 secretion and CYP19A1 expression, but stimulated the expression of FOS and JUN by signaling via the PCP pathway.…”

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confidence: 99%

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WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling

et al. 2015

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Whereas the roles of the canonical winglesstype MMTV (mouse mammary tumor virus) integration site family (WNT) signaling pathway in the regulation of ovarian follicle growth and steroidogenesis are now established, noncanonical WNT signaling in the ovary has been largely overlooked. Noncanonical WNTs, including WNT5a and WNT11, are expressed in granulosa cells (GCs) and are differentially regulated throughout follicle development, but their physiologic roles remain unknown. Using conditional gene targeting, we found that GC-specific inactivation of Wnt5a (but not Wnt11) results in the female subfertility associated with increased follicular atresia and decreased rates of ovulation. Microarray analyses have revealed that WNT5a acts to down-regulate the expression of FSH-responsive genes in vitro, and corresponding increases in the expression of these genes have been found in the GCs of conditional knockout mice. Unexpectedly, we found that WNT5a regulates its target genes not by signaling via the WNT/Ca 2+ or planar cell polarity pathways, but rather by inhibiting the canonical pathway, causing both b-catenin (CTNNB1) and cAMP responsive element binding (CREB) protein levels to decrease via a glycogen synthase kinase-3b-dependent mechanism. We further found that WNT5a prevents follicle-stimulating hormone and luteinizing protein from up-regulating the CTNNB1 and CREB proteins and their target genes, indicating that WNT5a functions as a physiologic inhibitor of gonadotropin signaling. Together, these findings identify WNT5a as a key regulator of follicle development and gonadotropin responsiveness.-Abedini, A., Zamberlam, G., Lapointe, E., Tourigny, C., Boyer, A., Paquet, M., Hayashi, K., Honda, H., Kikuchi, A., Price, C., Boerboom, D. WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling. FASEB J. 30, 1534-1547 (2016 The pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) represent the major endocrine regulators of ovarian function and are essential for follicle development beyond the secondary stage (1, 2). In addition to the endocrine level of control, follicle development is regulated by several paracrine and autocrine factors produced within the ovary itself. These factors notably include IGF-1, steroid hormones, prostaglandins, epidermal growth factor-like molecules and several TGF-b superfamily members, all of which are indispensable for normal ovarian function and female fertility. The gonadotropins can affect the expression and function of these intraovarian factors; conversely, these factors can modulate follicular responses to the gonadotropins (1-3).Recent studies have established the wingless-type MMTV (mouse mammary tumor virus) integration site (WNT) family of secreted glycoproteins as yet another class of signaling molecules that act to modulate and coordinate follicular responses to the gonadotropins and whose activities are indispensable for ovarian...

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Section: Discussionmentioning

confidence: 89%

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confidence: 99%

WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling

et al. 2015

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“…The abundance of Wnt members in growing follicles increases after human Chorionic gonadotropin administration in rodents (Hsieh, Mulders, Friis, Dharmarajan, & Richards, ). The role of WNT regulating the function of FSH on cattle follicular cells has also been described (Abedini, Zamberlam, Boerboom, & Price, ; Gupta et al, ). The importance of Wnt signaling in the ovary is demonstrated by the phenotype associated with Wnt4 ovarian conditional‐knockout mice, which exhibit a 75% reduction in antral follicles that is probably due to increased follicular atresia (Boyer, Lapointe et al, ).…”

Section: Introductionmentioning

confidence: 94%

Tankyrase inhibition regulates corpus luteum development and luteal function in gonadotropin‐treated rats

Accialini

Irusta

Bechis

et al. 2017

Molecular Reproduction Devel

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Tankyrases are physiological regulators of Axin, a protein involved in several cellular processes, including Wnt signaling. Here, we investigated the effect of a specific Tankyrase inhibitor (XAV939) in follicular-luteal dynamics, and its possible relationship with ovarian vascular development. Studies were designed to analyze the effect of intrabursa administration of XAV939 in gonadotropin-treated prepubertal rats. In particular, we examined follicle and corpus luteum development, steroidogenesis, angiogenic markers, and apoptotic parameters. We found that in vivo inhibition of Wnt signaling impaired corpus luteum development, with a decrease in the number of corpora lutea balanced by a high number of cysts; decreased circulating progesterone levels, likely due to a decrease in Steroidogenic acute regulatory protein content in the corpus luteum; and increased pro-apoptotic parameters. In addition, Extracellular signal-regulated kinase phosphorylation, Vascular endothelium growth factor 120 content, and endothelial cell area were diminished in corpora lutea of inhibitor-treated ovaries. Thus, Wnt/β-catenin signaling appears to participate in the regulation of corpus luteum development and luteal cell function.

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“…This involves activation of the p38 (MAPK14), ERK1/2 (MAPK3/1), and c-Jun N-terminal kinase (MAPK8) members of the MAP kinase (MAPK) family (Pestka 2008). As all these pathways are active in bovine granulosa cells (Evans & Martin 2000, Uzbekova et al 2009, Abedini et al 2015, we hypothesize that DON may activate one or more of these pathways to alter granulosa cell function. The objectives of this study were to determine the effects of DON on granulosa cell steroidogenesis and apoptosis in a non-luteinizing serum-free culture system, and to determine whether DON acts through typical RSR intracellular signaling pathways, including early response genes.…”

Section: Introductionmentioning

confidence: 99%

Effects of the mycotoxin deoxynivalenol on steroidogenesis and apoptosis in granulosa cells

Guerrero-Netro¹,

Chorfi²,

Price³

2015

Reproduction

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Mycotoxins can reduce fertility and development in livestock, notably in pigs and poultry, although the effect of most mycotoxins on reproductive function in cattle has not been established. One major mycotoxin, deoxynivalenol (DON), not only targets immune cells and activates the ribotoxic stress response (RSR) involving MAPK activation, but also inhibits oocyte maturation in pigs. In this study, we determined the effect of DON on bovine granulosa cell function using a serum-free culture system. Addition of DON inhibited estradiol and progesterone secretion, and reduced levels of mRNA encoding estrogenic (CYP19A1) but not progestogenic (CYP11A1 and STAR) proteins. Cell apoptosis was increased by DON, which also increased FASLG mRNA levels. The mechanism of action of DON was assessed by western blotting and PCR experiments. Addition of DON rapidly and transiently increased phosphorylation of MAPK3/1, and resulted in a more prolonged phosphorylation of MAPK14 (p38) and MAPK8 (JNK). Activation of these pathways by DON resulted in time-and dose-dependent increases in abundance of mRNA encoding the transcription factors FOS, FOSL1, EGR1, and EGR3. We conclude that DON is deleterious to granulosa cell function and acts through a RSR pathway.

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Non-canonical WNT5A is a potential regulator of granulosa cell function in cattle

Cited by 25 publications

References 59 publications

WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling

WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling

Tankyrase inhibition regulates corpus luteum development and luteal function in gonadotropin‐treated rats

Effects of the mycotoxin deoxynivalenol on steroidogenesis and apoptosis in granulosa cells

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