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Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis.

BACKGROUND & AIMS: Math1 (Atoh1) is a basic helix-loop-helix transcription factor important for intestinal secretory cell differentiation. We hypothesized that Math1 is important in cell fate commitment, and therefore mediates proliferative homeostasis and the adaptive response following intestinal resection in the adult intestine. METHODS: We generated mice with an intestine-specific mosaic deletion of Math1 (Math1(Delta intestine)) using the Cre/loxP system. Histologic analysis in adult Math1(Delta intestine) and wild-type littermates at baseline and following small bowel resection or sham surgery was performed. RESULTS: We observed loss of Paneth, goblet, and enteroendocrine cells in Math1-null crypts. In addition, aberrant activation of the Math1 promoter occurred in absorptive enterocytes derived from Math1-null crypts, suggesting a change in cell fate. Proliferation was increased but apoptosis unchanged in Math1-mutant crypts compared to adjacent wild-type crypts. Math1(Delta intestine) mice and wild-type littermates displayed similar physiologic adaptive responses to small bowel resection as measured by changes in body weight and ileal wet weight. In contrast, Math1-mutant crypts displayed a blunted adaptive response compared to adjacent wild-type crypts. CONCLUSIONS: We show that Math1 is essential for adult intestinal secretory cell production, and in its absence cells destined to a secretory phenotype instead adopt an absorptive phenotype. Subtle abnormalities of proliferation within Math1-null crypts in Math1(Delta intestine) mice were identified, together with a substantial defect in the adaptive response of Math1-null crypts following small bowel resection. Our results suggest that Math1 is critical for both cell fate determination within the intestinal epithelium and for regulation of the response to intestinal resection.

Pubmed ID: 17570220

Authors

  • Shroyer NF
  • Helmrath MA
  • Wang VY
  • Antalffy B
  • Henning SJ
  • Zoghbi HY

Journal

Gastroenterology

Publication Data

June 15, 2007

Associated Grants

  • Agency: NIMH NIH HHS, Id: F31 MH012444
  • Agency: NIDDK NIH HHS, Id: F32 DK63747
  • Agency: NIDDK NIH HHS, Id: K01 DK071686
  • Agency: NIDDK NIH HHS, Id: K01 DK071686
  • Agency: NIDDK NIH HHS, Id: K01 DK071686-01
  • Agency: NIDDK NIH HHS, Id: K08 DK067395
  • Agency: NIDDK NIH HHS, Id: P30 DK56338
  • Agency: NICHD NIH HHS, Id: P30 HD024064
  • Agency: NIDDK NIH HHS, Id: T32 DK07664

Mesh Terms

  • Adaptation, Physiological
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Body Weight
  • Cell Proliferation
  • Homeostasis
  • Ileum
  • Intestine, Small
  • Intestines
  • Male
  • Mice
  • Mice, Knockout
  • Organ Size