Evidence for a New Model of Intestinal Morphogenesis.

[摘要] During vertebrate intestinal development, coordinated morphogenetic movements between E12.5 and E16.5 transform the epithelial layer from a flat surface into evaginating villi and simultaneously generate an intestinal tube of considerable length.However, the genetic and cellular mechanisms driving growth and remodeling of the intestinal epithelium are poorly understood.The currently accepted model for epithelial remodeling proposes that: a) early epithelium is stratified and thickens by adding more cell layers; b) that lumen formation involves de novo apical surface generation at isolated secondary lumina; and c) that radial intercalation movements rearrange the epithelial surface into a single layer and generate intestinal length. Using advanced imaging tools and genetic mouse models, the work in this thesis disputes previous assumptions and presents a new model of intestinal morphogenesis. First, the E12.5-E14.5 epithelium is not stratified; rather, it is apicobasally polarized and pseudostratified. The tube grows in girth by progressive cellular elongation driven by actinomyosin and microtubule dependent processes. Second, lumen formation is actually an extension of apical surface from the primary lumen rather than by secondary lumen formation. The driver of luminal expansion is a specialized cell division that we call an extending division, or e-division, in which delivery of apical proteins to the cytokinetic furrow generates new apical surface. This event effectively expands the apical surface while placing the two daughter cells onto separate villi.We show that Shroom3, an actin binding protein, is required for the formation of a properly organized epithelial surface. Third, length generation does not involve radial intercalation. Instead, we present evidence that planar cell polarity (PCP) is involved in this process. Studies of genetic mouse mutants in known PCP genes, including Wnt5a, Vangl2, and Fat4, lead us to propose that defects in interkinetic nuclear migration as well as oriented cell division give rise to their short gut phenotypes and malformed villi. Together, these data support a new model of epithelial remodeling that has major implications for the mechanistic understanding of intestinal morphogenesis and length generation.

[发布机构] University of Michigan

[效力级别] Lumen Formation

[关键词] Intestinal Development;Lumen Formation;Epithelial Remodeling;Mouse Morphogenesis;Pseudostratified Epithelium;Intestinal Lengthening;Molecular;Cellular and Developmental Biology;Science;Cellular & Molecular Biology