Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis
Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis
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DOI：
10.1053/j.gastro.2007.03.047
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发表时间：
2007-06-01
期刊：
影响因子：
29.4
通讯作者：
Zoghbi, Huda Y.
中科院分区：
文献类型：
--
作者：
Shroyer, Noah F.;Helmrath, Michael A.;Zoghbi, Huda Y.
背景与目的：Math 1（Atoh 1）是一种基本的螺旋环-螺旋转录因子，在肠分泌细胞分化中起重要作用。我们假设Math 1在细胞命运承诺中很重要，因此介导了成人肠切除术后的增殖稳态和适应性反应。方法：我们使用Cre/loxP系统产生了Math 1（Math 1（Delta intestine））的丝氨酸特异性嵌合缺失小鼠。在基线和小肠切除术或假手术后，对成年Math 1（Delta肠）和野生型同窝仔进行组织学分析。结果：我们观察到的损失潘氏，杯状，肠内分泌细胞在Math 1无效的隐窝。此外，Math 1启动子的异常激活发生在来自Math 1无效隐窝的吸收性肠上皮细胞中，表明细胞命运的变化。与相邻的野生型隐窝相比，Math 1突变隐窝的增殖增加，但凋亡不变。Math 1（Delta intestine）小鼠和野生型同窝小鼠对小肠切除术表现出相似的生理适应性反应，通过体重和回肠湿重的变化进行测量。相比之下，Math 1突变的隐窝显示出钝化的适应性反应相比，相邻的野生型隐窝。结论：我们表明Math 1对于成人肠道分泌细胞的产生至关重要，在它缺失的情况下，注定具有分泌表型的细胞反而会采用吸收表型。在Math 1（Delta intesine）小鼠的Math 1-null隐窝内发现了微妙的增殖异常，以及小肠切除后Math 1-null隐窝适应性反应的实质性缺陷。我们的研究结果表明，Math 1是决定细胞命运的肠上皮细胞和调节肠切除术的反应是至关重要的。
Background & Aims: Math1 (Atoh1) is a basic helixloop-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 litter-mates 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 intesine) 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.