The epithelium of the small intestine undergoes a remarkable series of morphogenic changes during its development. The endodermally derived epithelial tube is initially comprised of a single layer of short columnar cells. Between E10.5 and E14.5, the epithelium takes on a progressively layered appearance, growing dramatically in girth. By E14.5, the tube appears to be up to 8 cells thick, with nuclei elongated in a radial fashion. In the 24 hours between E14.5 and E15.5, this apparently multilayered epithelium is dramatically remodeled, returning once again to a single layered sheet of epithelial cells. Concurrent with this remodeling, villi (fingerlike projections of the epithelial surface) are formed. Since villi represent the functional absorptive unit of the intestine, a detailed understanding of the mechanisms leading to their formation is an important goal. Moreover, the interval from E14 to E16 is a time of dramatic lengthening of the intestine; failure to establish proper intestinal length (as in idiopathic short bowel syndrome) can be life threatening. Data presented here challenge current thinking about the organization of the early intestinal epithelium and the mechanisms by which the epithelium is remodeled at E14.5. The Hypothesis/Working Model underlying this work is that: The early intestinal epithelium (E12.5-14.5) is pseudostratified and epithelial nuclei undergo interkinetic nuclear migration. At E14, oriented cell divisions extend luminal surface area. By E15, the apical surface of individual cells expands and cells shorten along their apical/basal axis, creating the first villi. Cell reshaping converts intestinal girth to length. The fidelity of these processes requires Wnt5a and planar cell polarity signaling. This proposal makes use of genetic mouse models as well as a novel intestinal explant culture system to mechanistically dissect the interconnected signaling and patterning events involved in these surface-generating processes.
The Specific Aims are designed to examine the shape/packing of epithelial cells in the early intestinal epithelium (Aim 1); to define the organization of cycling cells within the highly proliferative epithelium (Aim 2); to investigate the mechanisms by which epithelial cells gain apical surface beginning at E14.
5 (Aim 3); and to test the role of planar cell polarity signaling in epithelial cell arrangement, oriented cell division, apical surface determination and intestinal length generation (Aim 4). The outcome of these studies could have important implications for the bioengineering of fetal intestinal tissue and the treatment of short bowel syndrome in the fetus and newborn.
The huge surface area of the intestinal epithelium is critical for its efficient function in nutrient absorption, but little is known about how this surface area is generated in the fetus. This proposal delves deeply into the morphological and molecular processes that occur in the early mouse intestine and are required for the establishment of intestinal absorptive surface. The work could suggest therapeutic strategies for infants diagnosed with short bowel syndrome in utero.
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| Liu, Hong-Xiang; Grosse, Ann S; Iwatsuki, Ken et al. (2012) Separate and distinctive roles for Wnt5a in tongue, lingual tissue and taste papilla development. Dev Biol 361:39-56 |
| Grosse, Ann S; Pressprich, Mark F; Curley, Lauren B et al. (2011) Cell dynamics in fetal intestinal epithelium: implications for intestinal growth and morphogenesis. Development 138:4423-32 |
