Intestinal Morphogenesis and Differentiation

摘要 肠道具有简单的重复结构，这对其功能至关重要。吸收绒毛 是从肠隐窝分隔开的，肠隐窝容纳祖细胞并发挥功能。 作为干细胞龛。最近的研究在了解绒毛如何形成方面取得了进展 胚胎，但驱动出生后形态发生的细胞生物学机制， 地穴是未知的。我们已经进行了形态计量学和动态转录组学分析， 这为理解这一过程提供了一个框架。在这 建议我们集中在三个关键阶段的隐窝形成和功能。首先，我们讨论如何 隐窝在形态上与绒毛分隔开。我们的初步数据 这表明这对于绒毛图案化是必不可少的，并且使吸收的表面积最大化。 其次，我们分析了隐窝如何沿沿着隐窝/绒毛轴单轴扩张，以包装 肠道快速周转所需的祖细胞。最后，当细胞离开隐窝时， 必须成为具有吸收性的肠细胞。我们将分析转录调节因子的功能， 肠上皮细胞在细胞命运和组织结构中发挥重要作用。这些研究一起 将确定肠道干细胞生态位如何形成并定义刻板印象的作用 在干细胞功能、细胞命运决定和组织功能中的结构。

Abstract The intestine has a simple repeating architecture that is essential for its function. Absorptive villi are compartmentalized from the intestinal crypts, which house the progenitor cells and function as the stem cell niche. Recent studies have made inroads into understanding how villi form embryonically, but the cell biological mechanisms that drive the postnatal morphogenesis of crypts are not known. We have performed morphometric and dynamic transcriptomic analysis of crypt morphogenesis that has led to a framework for understanding this process. In this proposal we focus on three key stages of crypt formation and function. First, we address how the crypts become morphologically compartmentalized from the villi. Our preliminary data demonstrate that this is essential for villar patterning and maximizes surface area for absorption. Second, we analyze how crypts expand uniaxially along the crypt/villus axis in order to package progenitor cells required for the rapid turnover of the gut. Finally, as cells exit the crypt, most must become absorptive enterocytes. We will analyze functions of transcriptional regulators of enterocytes that play important roles in cell fate and tissue architecture. Together, these studies will establish how the intestinal stem cell niche forms and define roles for the stereotypical architecture in stem cell function, cell fate decisions, and tissue function.