Porcn-dependent Wnt signaling is not required prior to mouse gastrulation

Biechele, Steffen; Cockburn, Katie; Lanner, Fredrik; Cox, Brian; Rossant, Janet

doi:10.1242/dev.094458

Cited by 60 publications

(52 citation statements)

References 93 publications

(147 reference statements)

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“…To assess the role of the epithelial Wnts in intestinal homeostasis, we used a floxed allele of Porcn that is null for Wnt secretion after Cre-mediated excision (Biechele et al, 2013;Proffitt and Virshup, 2012 (Korinek et al, 1998;Zhong et al, 2012). Unexpectedly, Porcn Del /Villin-Cre pups were viable, appeared phenotypically normal, and suckled and weaned without difficulty.…”

Section: Normal Intestine Homeostasis After Complete Inhibition Of Epmentioning

confidence: 99%

“…Porcn flox mice (Biechele et al, 2013) were backcrossed to C57BL/6 mice at least for six generations. Porcn flox mice were crossed with BL/6 Villin-Cre mice.…”

Section: Mouse Strains and Drug Administrationmentioning

confidence: 99%

“…Porcn is encoded by a single copy gene on the X chromosome and has no closely related homologs in the genome. Zygotic Porcn mutants exhibit gastrulation failure leading to early embryonic lethality (Barrott et al, 2011;Biechele et al, 2011Biechele et al, , 2013. Several potent small molecule inhibitors of PORCN have been developed that phenocopy the biochemical effects of Porcn knockout, and may be of value in the treatment of Wnt-high diseases, including cancer and fibrotic disorders (Chen et al, 2009;Proffitt et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts

et al. 2014

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Wnt/β-catenin signaling supports intestinal homeostasis by regulating proliferation in the crypt. Multiple Wnts are expressed in Paneth cells as well as other intestinal epithelial and stromal cells. Ex vivo, Wnts secreted by Paneth cells can support intestinal stem cells when Wnt signaling is enhanced with supplemental R-Spondin 1 (RSPO1). However, in vivo, the source of Wnts in the stem cell niche is less clear. Genetic ablation of Porcn, an endoplasmic reticulum resident O-acyltransferase that is essential for the secretion and activity of all vertebrate Wnts, confirmed the role of intestinal epithelial Wnts in ex vivo culture. Unexpectedly, mice lacking epithelial Wnt activity (Porcn Del /Villin-Cre mice) had normal intestinal proliferation and differentiation, as well as successful regeneration after radiation injury, indicating that epithelial Wnts are dispensable for these processes. Consistent with a key role for stroma in the crypt niche, intestinal stromal cells endogenously expressing Wnts and Rspo3 support the growth of Porcn Del organoids ex vivo without RSPO1 supplementation. Conversely, increasing pharmacologic PORCN inhibition, affecting both stroma and epithelium, reduced Lgr5 intestinal stem cells, inhibited recovery from radiation injury, and at the highest dose fully blocked intestinal proliferation. We conclude that epithelial Wnts are dispensable and that stromal production of Wnts can fully support normal murine intestinal homeostasis.

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Section: Normal Intestine Homeostasis After Complete Inhibition Of Epmentioning

confidence: 99%

“…Porcn flox mice (Biechele et al, 2013) were backcrossed to C57BL/6 mice at least for six generations. Porcn flox mice were crossed with BL/6 Villin-Cre mice.…”

Section: Mouse Strains and Drug Administrationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts

et al. 2014

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“…In our PCR arrays of human CC, we found that both CTBP1 and PORCN were highly upregulated ( Figure 1A). CTNNB1-CTBP activates transcription of pro-proliferative WNT target genes (47), whereas PORCN is required for the palmitoylation of WNT ligands, thereby regulating their secretion (48,49). Thus, we specifically inhibited either the CTNNB1-CTBP interaction or the activity of PORCN in human CC cells in vitro with the small molecule ICG-001 or C-59, respectively.…”

Section: Loss Of Macrophage-derived Wnt Inhibits CC Growth In Vivomentioning

confidence: 99%

WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

Boulter¹,

Guest²,

Kendall³

et al. 2015

J. Clin. Invest.

233

242

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“…Porcupine-mediated acylation of Wnts occurs at a conserved serine residue and is necessary for the secretion of the Wnt proteins that include this serine residue. Experimental perturbation of Porcupine interferes with secretion of all Drosophila Wnts (except for WntD, which lacks the target serine residue) and all mouse and human Wnts (26)(27)(28)(29). Small chemical inhibitors of Porcupine recently have been proposed to be efficient agents that interfere systemically with Wnt signaling in clinical applications; here we used the Porcupine inhibitor C59 (30)(31)(32).…”

Section: System-wide Perturbation Of Wnt Signaling By a Porcupine Inhmentioning

confidence: 99%

Specific functions of the Wnt signaling system in gene regulatory networks throughout the early sea urchin embryo

Cui

Siriwon

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Wnt signaling affects cell-fate specification processes throughout embryonic development. Here we take advantage of the well-studied gene regulatory networks (GRNs) that control pregastrular sea urchin embryogenesis to reveal the gene regulatory functions of the entire Wnt-signaling system. Five wnt genes, three frizzled genes, two secreted frizzled-related protein 1 genes, and two Dickkopf genes are expressed in dynamic spatial patterns in the pregastrular embryo of Strongylocentrotus purpuratus. We present a comprehensive analysis of these genes in each embryonic domain. Total functions of the Wnt-signaling system in regulatory gene expression throughout the embryo were studied by use of the Porcupine inhibitor C59, which interferes with zygotic Wnt ligand secretion. Morpholino-mediated knockdown of each expressed Wnt ligand demonstrated that individual Wnt ligands are functionally distinct, despite their partially overlapping spatial expression. They target specific embryonic domains and affect particular regulatory genes. The sum of the effects of blocking expression of individual wnt genes is shown to equal C59 effects. Remarkably, zygotic Wnt-signaling inputs are required for only three general aspects of embryonic specification: the broad activation of endodermal GRNs, the regional specification of the immediately adjacent stripe of ectoderm, and the restriction of the apical neurogenic domain. All Wnt signaling in this pregastrular embryo is short range (and/or autocrine). Furthermore, we show that the transcriptional drivers of wnt genes execute important specification functions in the embryonic domains targeted by the ligands, thus connecting the expression and function of wnt genes by encoded crossregulatory interactions within the specific regional GRNs. embryonic interdomain signaling | developmental GRNs | Wnt system regulatory functions | Porcupine T he formation of spatial patterns of gene expression and the development of the body plan are controlled by gene regulatory networks (GRNs). Signaling interactions have a particular role in these networks, in that they provide the means of communication between cell-fate specification processes operating in separate cellular domains. The timing, location, and function of each signaling interaction is determined by GRN linkages that control the expression of signaling ligands and receptors as well as the expression of regulatory genes in response to a combination of signaling inputs and cell fate-specific transcription factors. Cell-fate specification GRNs active during pregastrular development of the sea urchin Strongylocentrotus purpuratus are particularly well understood. During the first 30 h of sea urchin embryogenesis, more than 15 gene-expression domains are formed, and specifically expressed regulatory genes have been identified for each domain. In most cases, the regulatory mechanisms determining their spatial expression patterns have been resolved. Thus, fairly complete GRN models have been constructed for the majority of cell-fate domains in ...

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Porcn-dependent Wnt signaling is not required prior to mouse gastrulation

Cited by 60 publications

References 93 publications

Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts

Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts

WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

Specific functions of the Wnt signaling system in gene regulatory networks throughout the early sea urchin embryo

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