Identification of the genes regulated by Wnt-4, a critical signal for commitment of the ovary

Naillat, Florence; Yan, Wenying; Karjalainen, Reijo; Liakhovitskaia, Anna; Samoylenko, Anatoly; Xu, Qi; Sun, Zhandong; Shen, Bairong; Medvinsky, Alexander; Quaggin, Susan E.; Vainio, Seppo

doi:10.1016/j.yexcr.2015.01.010

Cited by 37 publications

(29 citation statements)

References 59 publications

(102 reference statements)

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“…p21 has previously been shown as a direct transcriptional repressor of Wnt4 [ 48 ], but we observed the converse, that WNT4 is an upstream regulator of CDKN1A . Though our transcription factor screen did not identify a putative effector of WNT4 to suppress CDKN1A , a number of factors and/or pathways have been reported downstream of Wnt4 in murine tissues and thus may be functioning in ILC, including p38/Jnk [ 49 ], SF-1(NR5A1) [ 50 , 51 ], EAF1 and EAF2 [ 52 , 53 ], Runx-1 [ 54 ], and Fst [ 55 ]. Yu et al also demonstrated that noncanonical Wnt4 signaling could block ovariectomy-induced osteoporosis via inhibition of receptor activator of nuclear factor kB ligand-induced NF-kB signaling [ 56 ] (though we did not observe changes in NF-kB signaling upon siWNT4 in ILC-LTED; Fig.…”

Section: Discussionmentioning

confidence: 99%

WNT4 mediates estrogen receptor signaling and endocrine resistance in invasive lobular carcinoma cell lines

et al. 2016

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BackgroundInvasive lobular carcinoma (ILC) of the breast typically presents with clinical biomarkers consistent with a favorable response to endocrine therapies, and over 90 % of ILC cases express the estrogen receptor (ER). However, a subset of ILC cases may be resistant to endocrine therapies, suggesting that ER biology is unique in ILC. Using ILC cell lines, we previously demonstrated that ER regulates a distinct gene expression program in ILC cells, and we hypothesized that these ER-driven pathways modulate the endocrine response in ILC. One potential novel pathway is via the Wnt ligand WNT4, a critical signaling molecule in mammary gland development regulated by the progesterone receptor.MethodsThe ILC cell lines MDA-MB-134-VI, SUM44PE, and BCK4 were used to assess WNT4 gene expression and regulation, as well as the role of WNT4 in estrogen-regulated proliferation. To assess these mechanisms in the context of endocrine resistance, we developed novel ILC endocrine-resistant long-term estrogen-deprived (ILC-LTED) models. ILC and ILC-LTED cell lines were used to identify upstream regulators and downstream signaling effectors of WNT4 signaling.ResultsILC cells co-opted WNT4 signaling by placing it under direct ER control. We observed that ER regulation of WNT4 correlated with use of an ER binding site at the WNT4 locus, specifically in ILC cells. Further, WNT4 was required for endocrine response in ILC cells, as WNT4 knockdown blocked estrogen-induced proliferation. ILC-LTED cells remained dependent on WNT4 for proliferation, by either maintaining ER function and WNT4 regulation or uncoupling WNT4 from ER and upregulating WNT4 expression. In the latter case, WNT4 expression was driven by activated nuclear factor kappa-B signaling in ILC-LTED cells. In ILC and ILC-LTED cells, WNT4 led to suppression of CDKN1A/p21, which is critical for ILC cell proliferation. CDKN1A knockdown partially reversed the effects of WNT4 knockdown.ConclusionsWNT4 drives a novel signaling pathway in ILC cells, with a critical role in estrogen-induced growth that may also mediate endocrine resistance. WNT4 signaling may represent a novel target to modulate endocrine response specifically for patients with ILC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0748-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

WNT4 mediates estrogen receptor signaling and endocrine resistance in invasive lobular carcinoma cell lines

et al. 2016

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“…Compared to testis-related genes, however, genes expressed by the ovary have been studied far less extensively. The most important pathway of ovary development is the Wnt/beta-catenin signaling pathway, including Wnt family member 4 ( Wnt4 )[ 28 ], beta-catenin ( β-catenin )[ 29 ] and R-spondin1 ( Rspo1 )[ 30 ]. The roles of forkhead box L2 ( Foxl2 )[ 31 ] and the dosage-sensitive sex reversal-adrenal hypoplasia congenital ( AHC ) critical region on the X chromosomegene 1 ( Dax1 )[ 32 ] has also been extensively studied during ovarian development.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome analysis of sex-related genes in the blood clam Tegillarca granosa

et al. 2017

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BackgroundBlood clams (Tegillarca granosa) are one of the most commercial shellfish in China and South Asia with wide distribution in Indo-Pacific tropical to temperate estuaries. However, recent data indicate a decline in the germplasm of this species. Furthermore, the molecular mechanisms underpinning reproductive regulation remain unclear and information regarding genetic diversity is limited. Understanding the reproductive biology of shellfish is important in interpreting their embryology development, reproduction and population structure. Transcriptome sequencing (RNA-seq) rapidly obtains genetic sequence information from almost all transcripts of a particular tissue and currently represents the most prevalent and effective method for constructing genetic expression profiles.ResultsNon-reference RNA-seq, an Illumina HiSeq2500 Solexa system, and de novo assembly were used to construct a gonadal expression profile of the blood clam. A total of 63.75 Gb of clean data, with at least 89.46% of Quality30 (Q30), were generated which was then combined into 214,440 transcripts and 125,673 unigenes with a mean length of 1,122.63 and 781.30 base pairs (bp). In total, 27,325 genes were annotated by comparison with public databases. Of these, 2,140 and 2,070 differentially expressed genes (DEGs) were obtained (T05 T08 vs T01 T02 T04, T06 T07 vs T01 T02 T04; in which T01-T04 and T05-T08 represent biological replicates of individual female and male clams, respectively) and classified into two groups according to the evaluation of biological replicates. Then 35 DEGs and 5 sex-related unigenes, in other similar species, were investigated using qRT-PCR, the results of which were confirmed to data arising from RNA-seq. Among the DEGs, sex-related genes were identified, including forkhead box L2 (Foxl2), sex determining region Y-box (Sox), beta-catenin (β-catenin), chromobox homolog (CBX) and Sex-lethal (Sxl). In addition, 6,283 simple sequence repeats (SSRs) and 614,710 single nucleotide polymorphisms (SNPs) were identified from the RNA-seq results.ConclusionsThis study provided the first complete gonadal transcriptome data for the blood clam and allowed us to search many aspects of gene sequence information, not limited to gender. This data will improve our understanding of the transcriptomics and reproductive biology of the blood clam. Furthermore, molecular markers such as SSRs and SNPs will be useful in the analysis of genetic evolution, bulked segregant analysis (BSA) and genome-wide association studies (GWAS). Our transcriptome data will therefore provide important genetic information for the breeding and conservation of germplasm.

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“…The viewpoint was further supported by the proof that ATRA might stimulate the expression of RUNX1 in U937 cells (Tanaka et al., ). Simultaneously, deficiency of WNT4 in the embryonic ovary and administration of recombinant BMP2 protein to Jurkat cells led to the aberrant expression of RUNX1 (Yoshioka et al., ; Naillat et al., ). Further study evidenced that RUNX1 might serve as an intermediate to mediate the regulation of BMP2 and WNT4 on COL9A1 expression.…”

Section: Discussionmentioning

confidence: 99%

ATRA Signaling Regulates the Expression of COL9A1 through BMP2‐WNT4‐RUNX1 Pathway in Antler Chondrocytes

et al. 2017

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Although all-trans retinoic acid (ATRA) is involved in the regulation of cartilage growth and development, its regulatory mechanisms remain unknown. Here, we showed that ATRA could induce the expression of COL9A1 in antler chondrocytes. Silencing of cellular retinoic acid binding protein 2 (CRABP2) could impede the ATRA-induced upregulation of COL9A1, whereas overexpression of CRABP2 presented the opposite effect. RARα agonist Am80 induced the expression of COL9A1, whereas treatment with RARα antagonist Ro 41-5253 or RXRα small-interfering RNA (siRNA) caused an obvious blockage of ATRA on COL9A1. In antler chondrocytes, CYP26A1 and CYP26B1 weakened the sensitivity of ATRA to COL9A1. Simultaneously, Bone morphogenetic protein 2 (BMP2) and WNT4 mediated the regulation of ATRA on COL9A1 expression. Knockdown of WNT4 could abrogate the inhibitory effect of BMP2 overexpression on COL9A1. Conversely, constitutive expression of WNT4 reversed the upregulation of COL9A1 elicited by BMP2 siRNA. Together these data indicated that WNT4 might act downstream of BMP2 to mediate the effect of ATRA on COL9A1 expression. Further analysis evidenced that attenuation of runt-related transcription factor 1 (RUNX1) could prevent the stimulation of ATRA on COL9A1 expression, while exogenous rRUNX1 further enhanced this effectiveness. Moreover, RUNX1 might serve as an intermediate to mediate the regulation of BMP2 and WNT4 on COL9A1 expression. Collectively, ATRA signaling might regulate the expression of COL9A1 through BMP2-WNT4-RUNX1 pathway.

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Identification of the genes regulated by Wnt-4, a critical signal for commitment of the ovary

Cited by 37 publications

References 59 publications

WNT4 mediates estrogen receptor signaling and endocrine resistance in invasive lobular carcinoma cell lines

WNT4 mediates estrogen receptor signaling and endocrine resistance in invasive lobular carcinoma cell lines

Transcriptome analysis of sex-related genes in the blood clam Tegillarca granosa

ATRA Signaling Regulates the Expression of COL9A1 through BMP2‐WNT4‐RUNX1 Pathway in Antler Chondrocytes

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