Enteroendocrine precursors differentiate independently of Wnt and form serotonin expressing adenomas in response to active beta-catenin.
Wnt signaling is required for the maintenance of intestinal stem cells and self-renewal of the intestinal epithelium. Intestinal cancers are frequently associated with mutations that activate the Wnt pathway. The role of Wnt signaling on differentiation of lineage-specific precursors in the intestine is not well characterized. Here, we show that specification of enteroendocrine but not Paneth cells occurs independently of Wnt signals by conditional deletion of beta-catenin in immature cells expressing the transcription factor, neurogenin 3. In addition, we determined whether neurogenin 3-expressing cells respond to abnormal Wnt signaling. Activation of the Wnt pathway by conditionally deleting exon 3 of the beta-catenin gene at an early stage of enteroendocrine cell differentiation induced small-intestinal adenomas expressing serotonin, a feature not previously described in other tumors induced by Wnt in mice. In contrast, excision of exon 3 of beta-catenin at a later stage of enteroendocrine differentiation did not produce tumors. These results provide direct evidence that some intestinal lineages are specified independently of the Wnt pathway and may lead to a better understanding of the spectrum of neuroendocrine differentiation frequently seen in human gastrointestinal cancer.
Wang
Yang
Y
Division of Gastroenterology, GRASP Digestive Disease Center, Tufts-New England Medical Center, Boston, MA 02111, USA.
Giel-Moloney
Maryann
M
Rindi
Guido
G
Leiter
Andrew B
AB
D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D019858:Enteroendocrine Cells / Q000166:cytology* / Q000473:pathology; D005091:Exons / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D017384:Sequence Deletion; D012701:Serotonin / Q000096:biosynthesis* / Q000235:genetics; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D012701:Serotonin; D051153:Wnt Proteins; D051176:beta Catenin; C495270:CTNNB1 protein, human; C498695:NEUROG3 protein, human