Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium

Gerbe, François; Es, Johan H. van; Makrini, Leila; Brulin, Bénédicte; Mellitzer, Georg; Robine, Sylvie; Romagnolo, Béatrice; Shroyer, Noah F.; Bourgaux, Jean–François; Pignodel, C; Clevers, Hans; Jay, Philippe

doi:10.1083/jcb.201010127

Cited by 338 publications

(450 citation statements)

References 63 publications

Supporting

Mentioning

398

Contrasting

Unclassified

Order By: Relevance

“…understood (Gerbe et al, 2011;Bjerknes et al, 2012). We found here that Elp3 is critical for Tuft cell differentiation, as its absence leads to dramatic reduction of Dclk1 + Tuft cells in the intestinal epithelium.…”

Section: Discussionmentioning

confidence: 73%

“…Tuft cells originate from poorly characterized tuft cell progenitors, are enriched in acetylated α-tubulin, and show characteristic microtubule and actin bundles located at the cell apex exposed to the luminal environment (Gerbe et al, 2011(Gerbe et al, , 2012. They are distinct from intestinal secretory cells, as transcription factors such as Neurog3, Sox9, and Spdef are dispensable for their generation (Gerbe et al, 2011;Bjerknes et al, 2012).…”

mentioning

confidence: 99%

“…They are distinct from intestinal secretory cells, as transcription factors such as Neurog3, Sox9, and Spdef are dispensable for their generation (Gerbe et al, 2011;Bjerknes et al, 2012). Tuft cells specifically express Doublecortin-like kinase 1 (Dclk1; also referred to as Dcamkl-1) as well as the transcription factor Gfi1B (Bjerknes et al, 2012;Gerbe et al, 2012).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine

Ladang¹,

Rapino²,

Heukamp³

et al. 2015

J Cell Biol

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 73%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine

Ladang¹,

Rapino²,

Heukamp³

et al. 2015

J Cell Biol

View full text Add to dashboard Cite

“…When possible, 1 to 2 tumors (≈2-3mm) were removed from the jejunum and kept in RNAlater at −80°C for further RNA extraction. Tissue fixation and immunohistochemistry on thin sections of paraffin-embedded tissue were performed essentially as described previously (35).…”

Section: Methodsmentioning

confidence: 99%

Essential requirement for β-arrestin2 in mouse intestinal tumors with elevated Wnt signaling

Bonnans

Flacelière

Grillet

et al. 2012

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

View full text Add to dashboard Cite

β-Arrestins (Arrb) participate in the regulation of multiple signaling pathways, including Wnt/β-catenin, the major actor in human colorectal cancer initiation. To better understand the roles of Arrb in intestinal tumorigenesis, a reverse genetic approach (Arrb −/− ) and in vivo siRNA treatment were used in Apc Δ14/+ mice. Mice with Arrb2 depletion (knockout and siRNA) developed only 33% of the tumors detected in their Arrb2-WT littermates, whereas Arrb1 depletion remained without significant effect. These remaining tumors grow normally and are essentially Arrb2-independent. Unsupervised hierarchical clustering analysis showed that they clustered with 25% of Apc Δ14/+ ;Arrb2 +/+ tumors. Genes overexpressed in this subset reflect a high interaction with the immune system, whereas those overexpressed in Arrb2-dependent tumors are predominantly involved in Wnt signaling, cell adhesion, migration, and extracellular matrix remodeling. The involvement of Arrb2 in intestinal tumor development via the regulation of the Wnt pathway is supported by ex vivo and in vitro experiments using either tumors from Apc Δ14/+ mice or murine Apc Min/+ cells. Indeed, Arrb2 siRNAs decreased the expression of Wnt target genes in cells isolated from 12 of 18 tumors from Apc Δ14/+ mice. In Apc Min/+ cells, Arrb2 siRNAs completely reversed the increased Wnt activity and colony formation in soft agar induced by Apc siRNA treatment, whereas they did not affect these parameters in basal conditions or in cells expressing constitutively active β-catenin. We demonstrate that Arrb2 is essential for the initiation and growth of intestinal tumors displaying elevated Wnt pathway activity and identify a previously unsuspected molecular heterogeneity among tumors induced by truncating Apc mutations.tumor initiation | carcinogenesis

show abstract

“…This continuous regeneration is carried out by an active intestinal stem cell population, which gives rise to proliferating progenitors that differentiate into the five types of epithelial cells. These include two lineages: an absorptive one composed of enterocytes; and a secretory one composed of goblet cells, enteroendocrine cells, Paneth cells, and the recently characterized tuft cells (2). Differentiation of all of these cell types takes place during migration from the crypts to the villi, except Paneth cells, which complete their differentiation at the crypt base intercalated between a population of a particular type of stem cell: the crypt base columnar cells (CBCs).…”

mentioning

confidence: 99%

Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1)

Durand

Donahue

Peignon

et al. 2012

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

Self Cite

279

244

View full text Add to dashboard Cite

Intestinal epithelium has the capacity to self-renew and generate differentiated cells through the existence of two types of epithelial stem cells: active crypt base columnar cells (CBCs) and quiescent +4 cells. The behaviors of these cells are regulated both by intrinsic programs and by extrinsic signals sent by neighboring cells, which define the niche. It is clear that the β-catenin pathway acts as an essential intrinsic signal for the maintenance and proliferation of CBC, and it was recently proposed that Paneth cells provide a crucial niche by secreting Wingless/Int (Wnt) ligands. Here, we examined the effect of disrupting the intestinal stem cell niche by inducible deletion of the transcription factor Math1 (Atoh1), an essential driver of secretory cell differentiation. We found that complete loss of Paneth cells attributable to Math1 deficiency did not perturb the crypt architecture and allowed the maintenance and proliferation of CBCs. Indeed, Math1-deficient crypt cells tolerated in vivo Paneth cell loss and maintained active β-catenin signaling but could not grow ex vivo without exogenous Wnt, implying that, in vivo, underlying mucosal cells act as potential niche. Upon irradiation, Math1-deficient crypt cells regenerated and CBCs continued cycling. Finally, CBC stem cells deficient in adenomatous polyposis coli (Apc) and Math1 were able to promote intestinal tumorigenesis. We conclude that in vivo, Math1-deficient crypts counteract the absence of Paneth cell-derived Wnts and prevent CBC stem cell exhaustion.

show abstract

Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium

Abstract: Tuft cells represent a fourth type of intestinal secretory cell that constitutes the primary source of endogenous intestinal opioids and are the only epithelial cell that constitutively express cyclooxygenases.

Cited by 338 publications

References 63 publications

Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine

Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine

Essential requirement for β-arrestin2 in mouse intestinal tumors with elevated Wnt signaling

Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1)

Contact Info

Product

Resources

About