Ets Transcription Factors Control Epithelial Maturation and Transit and Crypt-Villus Morphogenesis in the Mammalian Intestine
Ets Transcription Factors Control Epithelial Maturation and Transit and Crypt-Villus Morphogenesis in the Mammalian Intestine
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DOI：
10.2353/ajpath.2009.080409
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发表时间：
2009-04-01
影响因子：
6
通讯作者：
Gutierrez-Hartmannt, Arthur
中科院分区：
文献类型：
--
作者：
Jedlicka, Paul;Sui, Xiaomei;Gutierrez-Hartmannt, Arthur
Ets转录因子家族的成员在发育和成熟的哺乳动物肠道中广泛表达，但其生物学功能仍然主要未知。我们使用显性阻遏物转基因方法来探测上皮Ets因子在小肠的功能单位--隐窝-绒毛单位的稳态中的功能。我们发现，在小肠上皮细胞中靶向表达由Engrailed阻遏物结构域和Erm DNA结合结构域（En/Erm）组成的融合蛋白，导致正常的隐窝-绒毛稳态明显破坏，包括上皮成熟的细胞自主性障碍，上皮转运增加，严重的绒毛畸形和隐窝畸形。上皮成熟障碍是独立的TGF β RII水平的调节，在相反的Ets介导的上皮分化在发展过程中，而Cdx 2表达的调节可能发挥作用。绒毛畸形是独立的改变，在隐窝绒毛边界和不适当的β-连环蛋白激活，因此似乎代表了一种新的机制控制绒毛建筑组织。En/Erm表达的动物镶嵌分析表明，隐窝非自主机制是隐窝畸形表型的基础。因此，我们的研究揭示了新的Ets调节途径的体内肠道稳态。有趣的是，整体En/Erm表型的隐窝-绒毛稳态紊乱是一致的，最近确定的Ets功能的限制肠上皮肿瘤的发生。(Am J Pathol 2009，174：1280-1290; DOI：10.2353/ajpath.2009.080409）
Members of the Ets transcription factor family are widely expressed in both the developing and mature mammalian intestine, but their biological functions remain primarily uncharacterized. We used a dominant repressor transgene approach to probe the function of epithelial Ets factors in the homeostasis of the crypt-villus unit, the functional unit of the small intestine. We show that targeted expression in small intestinal epithelium of a fusion protein composed of the Engrailed repressor domain and the Erm DNA-binding domain (En/Erm) results in marked disruption of normal crypt-villus homeostasis, including a cell-autonomous disturbance of epithelial maturation, increased epithelial transit, severe villus dysmorphogenesis, and crypt dysmorphogenesis. The epithelial maturation disturbance is independent of the regulation of TGF beta RII levels, in contrast to Ets-mediated epithelial differentiation during development; rather, regulation of Cdx2 expression may play a role. The villus dysmorphogenesis is independent of alterations in the crypt-villus boundary and inappropriate beta-catenin activation, and thus appears to represent a new mechanism controlling villus architectural organization. An Analysis of animals mosaic for En/Erm expression suggests that crypt nonautonomous mechanisms underlie the crypt dysmorphogenesis phenotype. Our studies thus uncover novel Ets-regulated pathways of intestinal homeostasis in vivo. Interestingly, the overall En/Erm phenotype of disturbed crypt-villus homeostasis is consistent with recently identified Ets function(s) in the restriction of intestinal epithelial tumorigenesis. (Am J Pathol 2009, 174:1280-1290; DOI: 10.2353/ajpath.2009.080409)