Shroyer Noah F, Helmrath Michael A, Wang Vincent Y-C, Antalffy Barbara, Henning Susan J, Zoghbi Huda Y
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Gastroenterology. 2007 Jun;132(7):2478-88. doi: 10.1053/j.gastro.2007.03.047. Epub 2007 Mar 24.
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.
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.
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.
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.
Math1（Atoh1）是一种对肠道分泌细胞分化至关重要的碱性螺旋-环-螺旋转录因子。我们推测Math1在细胞命运决定中起重要作用，因此介导成年肠道切除术后的增殖稳态和适应性反应。
我们使用Cre/loxP系统构建了肠道特异性Math1镶嵌缺失的小鼠（Math1(Δ肠道)）。对成年Math1(Δ肠道)小鼠和野生型同窝小鼠在基线时以及小肠切除或假手术后进行组织学分析。
我们观察到Math1缺失的隐窝中潘氏细胞、杯状细胞和肠内分泌细胞缺失。此外，在源自Math1缺失隐窝的吸收性肠上皮细胞中发生了Math1启动子的异常激活，提示细胞命运发生改变。与相邻野生型隐窝相比，Math1突变隐窝中的增殖增加但凋亡未改变。通过体重和回肠湿重变化测量，Math1(Δ肠道)小鼠和野生型同窝小鼠对小肠切除显示出相似的生理适应性反应。相比之下，Math1突变隐窝与相邻野生型隐窝相比显示出减弱的适应性反应。
我们表明Math1对成年肠道分泌细胞的产生至关重要，在其缺失时，注定为分泌表型的细胞转而采用吸收表型。在Math1(Δ肠道)小鼠的Math1缺失隐窝中鉴定出增殖的细微异常，以及小肠切除后Math1缺失隐窝适应性反应的实质性缺陷。我们的结果表明Math1对于肠道上皮内的细胞命运决定以及肠道切除反应的调节都至关重要。
