WNT4 is expressed in human fetal and adult ovaries and its signaling contributes to ovarian cell survival

Jääskeläinen, Minna; Prunskaite‐Hyyryläinen, Renata; Naillat, Florence; Parviainen, Helka; Anttonen, Mikko; Heikinheimo, Markku; Liakka, Annikki; Ola, Roxana; Vainio, Seppo; Vaskivuo, Tommi; Tapanainen, Juha S.

doi:10.1016/j.mce.2009.11.013

Cited by 37 publications

(37 citation statements)

References 28 publications

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“…282 and 283). In granulosa cells of the adult ovary, the expression of WNT2 (284) and WNT4 (285,286) has been observed. WNT2 binds the frizzled-9 receptor (FZD9; cluster of differentiation 349, CD349) to signal via the canonical pathway in cultured human cumulus cells (287).…”

Section: Wnt/␤-cateninmentioning

confidence: 99%

Molecular Pathogenesis of Granulosa Cell Tumors of the Ovary

2012

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Granulosa cell tumors of the ovary (GCT) comprise a distinct subset of ovarian cancers that account for approximately 5% of all ovarian malignancies. They are thought to arise from normal proliferating granulosa cells of the late preovulatory follicle and exhibit many morphological and biochemical features of these cells. GCT are distinct from other ovarian carcinomas in their hormonal activity; their ability to secrete estrogen, inhibin, and Müllerian inhibiting substance accounts for some of the clinical manifestations of the disease and also provides useful tumor markers for disease surveillance. Although considered to be of low malignant potential, GCT are commonly associated with slow, indolent disease progression, and frequent yet long delays to tumor recurrence are characteristic of this disease. Unlike the more intensely investigated epithelial ovarian tumors, relatively little is known about the molecular and genetic changes that give rise to GCT. To date, many investigations have centered around pathways known to be involved in normal granulosa cell proliferation, including those activated by FSH receptor stimulation. Most recently, the finding that approximately 97% of adult GCT harbor a somatic missense mutation in the FOXL2 gene (c.402C→G; p.C134W) represents an exciting advancement in the field of GCT research. The high frequency with which the mutation occurs in adult GCT, along with its absence from juvenile GCT and other human malignancies is suggestive of an oncogenic or gain-of-function mutation and, indeed, that the mutation is pathognomonic for adult GCT. In this review, we explore the implications of this finding and the most recent work characterizing molecular pathways of potential pathogenetic significance in GCT.

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Section: Wnt/␤-cateninmentioning

confidence: 99%

Molecular Pathogenesis of Granulosa Cell Tumors of the Ovary

2012

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“…20 In addition, Tomato+ cells were observed in the stromal cells of intestine and stomach ( Figure 1A). Finally, we used Wnt4 GCE/+ ; R26 tdTomato/+ to detect Tomato+ cells in choroid plexus, hepatic stellate cells, epithelial and stromal cells of the ureter, and ovaries 21 (Supplemental Figure 2 and data not shown). These data indicate that Wnt4 GCE/+ ;R26 tdTomato/+ represent endogenous Wnt4 expression and can be used to study Wnt4 in a variety of tissues.…”

Section: Wnt4 Expression Is Restricted To Papillary Principal Cells Amentioning

confidence: 99%

Wnt4/β−Catenin Signaling in Medullary Kidney Myofibroblasts

DiRocco

Kobayashi

Taketo

et al. 2013

Journal of the American Society of Nephrology

155

136

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Injury to the adult kidney induces a number of developmental genes thought to regulate repair, including Wnt4. During kidney development, early nephron precursors and medullary stroma both express Wnt4, where it regulates epithelialization and controls smooth muscle fate, respectively. Expression patterns and roles for Wnt4 in the adult kidney, however, remain unclear. In this study, we used reporters, lineage analysis, and conditional knockout or activation of the Wnt/b-catenin pathway to investigate Wnt4 in the adult kidney. Proliferating, medullary, interstitial myofibroblasts strongly expressed Wnt4 during renal fibrosis, whereas tubule epithelia, except for the collecting duct, did not. Exogenous Wnt4 drove myofibroblast differentiation of a pericyte-like cell line, suggesting that Wnt4 might regulate pericyte-to-myofibroblast transition through autocrine signaling. However, conditional deletion of Wnt4 in interstitial cells did not reduce myofibroblast proliferation, cell number, or myofibroblast gene expression during fibrosis. Because the injured kidney expresses multiple Wnt ligands that might compensate for the absence of Wnt4, we generated a mouse model with constitutive activation of canonical Wnt/b-catenin signaling in interstitial pericytes and fibroblasts. Kidneys from these mice exhibited spontaneous myofibroblast differentiation in the absence of injury. Taken together, Wnt4 expression in renal fibrosis defines a population of proliferating medullary myofibroblasts. Although Wnt4 may be dispensable for myofibroblast transformation, canonical Wnt signaling through b-catenin stabilization is sufficient to drive spontaneous myofibroblast differentiation in interstitial pericytes and fibroblasts, emphasizing the importance of this pathway in renal fibrosis.

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“…In humans, RSPO1 is expressed between 6 and 9 weeks after conception in the fetal ovary (Tomaselli et al 2011), whereas WNT4 is detected in both the fetal and adult ovary at different follicular stages (Jaaskelainen et al 2010) as in mice. In marsupials, the WNT4 mRNA level increases after birth, reaching a peak of expression by days 9-13 post partum when the ovarian cortex and medulla become distinguishable (Yu et al 2006).…”

Section: Mammalsmentioning

confidence: 99%

R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation

Chassot¹,

Gillot²,

Chaboissier³

2014

Reproduction

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Sex differentiation is a unique developmental process. Starting from a bipotential gonad, it gives rise to the ovary and the testis, two highly specialized organs that differ morphologically and physiologically despite sharing common reproductive and endocrine functions. This highlights the specific plasticity of the gonadal precursors and the existence of complex antagonistic genetic regulation. Mammalian sex determination is controlled by paternal transmission of the Y-linked gene, sex-determining region Y (SRY). Using mouse models, it has been shown that the main role of Sry is to activate the expression of the transcription factor Sox9; either one of these two genes is necessary and sufficient to allow testicular development through Sertoli cell differentiation. Thus, defects in SRY/Sry and/or SOX9/Sox9 expression result in male-to-female sex reversal of XY individuals. Molecular mechanisms governing ovarian differentiation remained unknown for a long time, until the discovery of the roles of R-spondin1 (RSPO1) and WNT4. In XX individuals, activation of the b-catenin signaling pathway by the secreted proteins RSPO1 and WNT4 is required to allow granulosa cell differentiation and, in turn, ovarian differentiation. Thus, mutations in RSPO1 result in female-to-male sex reversal of XX patients, and mouse models have allowed the identification of genetic cascades activated by RSPO1 and WNT4 to regulate ovarian development. In this review, we will discuss the respective roles of RSPO1, WNT4, and the b-catenin signaling pathway during ovarian differentiation in mice.Reproduction (2014) 148 R97-R110

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WNT4 is expressed in human fetal and adult ovaries and its signaling contributes to ovarian cell survival

Cited by 37 publications

References 28 publications

Molecular Pathogenesis of Granulosa Cell Tumors of the Ovary

Molecular Pathogenesis of Granulosa Cell Tumors of the Ovary

Wnt4/β−Catenin Signaling in Medullary Kidney Myofibroblasts

R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation

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