Loss of Sonic Hedgehog Leads to Alterations in Intestinal Secretory Cell Maturation and Autophagy

Gagné‐Sansfaçon, Jessica; Allaire, Joannie M.; Jones, Christine M.; Boudreau, François; Perreault, Nathalie

doi:10.1371/journal.pone.0098751

Cited by 30 publications

(25 citation statements)

References 57 publications

(101 reference statements)

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“…In the murine colon, Ihh messenger RNA expression exceeds that of Shh by several orders of magnitude ( Supplementary Fig. 2a and refs 22 , 23 ), and an Shh conditional knockout model revealed a limited phenotype strictly confined to the terminal ileum 24 . To assess whether reduced Hh signalling can promote malignant transformation in the colon, we used a genetic model in which the main intestinal ligand, Ihh , can be knocked out by Tamoxifen (Tam) administration to VillinCreER;Ihh flox/flox ;R26-LSL-ZsGreen mice (hereafter Ihh ΔVil ), simultaneously activating expression of a conditional fluorescent reporter.…”

Section: Resultsmentioning

confidence: 99%

Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth

et al. 2016

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A role for Hedgehog (Hh) signalling in the development of colorectal cancer (CRC) has been proposed. In CRC and other solid tumours, Hh ligands are upregulated; however, a specific Hh antagonist provided no benefit in a clinical trial. Here we use Hh reporter mice to show that downstream Hh activity is unexpectedly diminished in a mouse model of colitis-associated colon cancer, and that downstream Hh signalling is restricted to the stroma. Functionally, stroma-specific Hh activation in mice markedly reduces the tumour load and blocks progression of advanced neoplasms, partly via the modulation of BMP signalling and restriction of the colonic stem cell signature. By contrast, attenuated Hh signalling accelerates colonic tumourigenesis. In human CRC, downstream Hh activity is similarly reduced and canonical Hh signalling remains predominantly paracrine. Our results suggest that diminished downstream Hh signalling enhances CRC development, and that stromal Hh activation can act as a colonic tumour suppressor.

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Section: Resultsmentioning

confidence: 99%

Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth

et al. 2016

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“…We are unaware of studies in other organisms that have uncovered direct roles for either gli-1 or RREB2 in goblet cells. However, in mice, modulation of Sonic Hedgehog (an upstream activator of Gli-family TFs) levels affects goblet cell numbers (135, 136), and RREB1 cooperatively regulates expression of the peptide hormone secretin in enteroendocrine cells (137). By contrast, in the Drosophila midgut, Hedgehog (Hh) signaling promotes intestinal stem cell proliferation (138), while the RREB-1 ortholog hindsight/pebbled suppresses midgut intestinal stem cell proliferation and is required for differentiation of absorptive enterocytes (139).…”

Section: Discussionmentioning

confidence: 99%

Cell-type diversity and regionalized gene expression in the planarian intestine revealed by laser-capture microdissection transcriptome profiling

Forsthoefel

Cejda

Khan

et al. 2019

Preprint

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Organ regeneration requires precise coordination of new cell differentiation and remodeling of uninjured tissue to faithfully re-establish organ morphology and function. An atlas of gene expression and cell types in the uninjured state is therefore an essential pre-requisite for understanding how damage is repaired. Here, we use laser-capture microdissection (LCM) and RNA-Seq to define the transcriptome of the intestine of Schmidtea mediterranea, a planarian flatworm with exceptional regenerative capacity. Bioinformatic analysis of 1,844 intestine-enriched transcripts suggests extensive conservation of digestive physiology with other animals, including humans. Comparison of the intestinal transcriptome to purified absorptive intestinal cell (phagocyte) and published single-cell expression profiles confirms the identities of known intestinal cell types, and also identifies hundreds of additional transcripts with previously undetected intestinal enrichment. Furthermore, by assessing the expression patterns of 143 transcripts in situ, we discover unappreciated mediolateral regionalization of gene expression and cell-type diversity, especially among goblet cells. Demonstrating the utility of the intestinal transcriptome, we identify 22 intestine-enriched transcription factors, and find that several have distinct functional roles in the regeneration and maintenance of goblet cells. Furthermore, depletion of goblet cells inhibits planarian feeding and reduces viability. Altogether, our results show that LCM is a viable approach for assessing tissue-specific gene expression in planarians, and provide a new resource for further investigation of digestive tract regeneration, the physiological roles of intestinal cell types, and axial polarity.

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“…Genomic DNA was isolated from enrichment of epithelial and mesenchymal compartments of the stomach of 1-year-old mice by an adaptation of the MatriSperse dissociation method 59 60 . Briefly, mice were sacrificed and the stomach was collected.…”

Section: Methodsmentioning

confidence: 99%

Loss of mesenchymal bone morphogenetic protein signaling leads to development of reactive stroma and initiation of the gastric neoplastic cascade

Roy

Allaire

Ouellet

et al. 2016

Sci Rep

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Bmps are morphogens involved in various gastric cellular functions. Studies in genetically-modified mice have shown that Bmp disruption in gastric epithelial and stromal cell compartments leads to the development of tumorigenesis. Our studies have demonstrated that abrogation of gastric epithelial Bmp signaling alone was not sufficient to recapitulate the neoplastic features associated with total gastric loss of Bmp signaling. Thus, epithelial Bmp signaling does not appear to be a key player in gastric tumorigenesis initiation. These observations suggest a greater role for stromal Bmp signaling in gastric polyposis initiation. In order to identify the specific roles played by mesenchymal Bmp signaling in gastric homeostasis, we generated a mouse model with abrogation of Bmp signaling exclusively in the gastro-intestinal mesenchyme (Bmpr1aΔMES). We were able to expose an unsuspected role for Bmp loss of signaling in leading normal gastric mesenchyme to adapt into reactive mesenchyme. An increase in the population of activated-fibroblasts, suggesting mesenchymal transdifferentiation, was observed in mutant stomach. Bmpr1aΔMES stomachs exhibited spontaneous benign polyps with presence of both intestinal metaplasia and spasmolytic-polypeptide-expressing metaplasia as early as 90 days postnatal. These results support the novel concept that loss of mesenchymal Bmp signaling cascade acts as a trigger in gastric polyposis initiation.

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Loss of Sonic Hedgehog Leads to Alterations in Intestinal Secretory Cell Maturation and Autophagy

Cited by 30 publications

References 57 publications

Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth

Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth

Cell-type diversity and regionalized gene expression in the planarian intestine revealed by laser-capture microdissection transcriptome profiling

Loss of mesenchymal bone morphogenetic protein signaling leads to development of reactive stroma and initiation of the gastric neoplastic cascade

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