Mechanical and molecular factors underlying morphogenesis of the intestinal villi

Harvard Medical School, Boston MA

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Abstract

DESCRIPTION (provided by applicant): In higher vertebrates, the luminal surface of the small intestine consists of a specialized epithelium adapted to enhance nutrient absorption through the presence of numerous villi, finger-like projections that dramatically increase surface area in the gut. Cells of the villus have a lifetime of only 3 to 4 days, after which they are replaced by cells originating at the villus base in crypts, stem cell niches within invaginations of the epithelium. Wnt signaling plays an important role in regulating the differentiation and proliferation of these stem cells, and abnormal Wnt-signaling in these structures has been strongly associated with gastrointestinal cancers. At the onset of villi morphogenesis, the gut tube lumen is initially smooth, and the inner endodermal layer represents a uniform pool of epithelial stem cells. Villi morphogenesis proceeds through striking transformations in luminal topography, whereby a number of straight longitudinal ridges form, then become wavy, or kinked, and finally villi begin to form at the points of inflection in these ridges. By the end of this transformation, stem cell populations have become restricted to intervillus regions where the crypts will form. These transformations generate physical patterns consistent with compression induced bi-directional buckling of an elastic material, suggesting that mechanical forces may plan an important role in villi morphogenesis. Therefore, the objective of the proposed work is to determine the physical forces that drive topographical changes of the midgut endoderm, and what role this unique topography plays in patterning the intestinal villi. It is hypothesized that physical forces generated in the surrounding mesodermal layers drive compression- induced buckling in the endoderm, and that this displaces endodermal cells within a morphogen gradient, providing positional cues that guide differentiation into mature villi. The following aims are proposed: Specific Aim 1: Determine the role of active force generation in the formation and kinking of pre-villus longitudinal ridges. Specific Aim 2: Determine the expression pattern of Wnts and related genes in the midgut mesoderm and endoderm throughout the stages of villus morphogenesis. Specific Aim 3: Determine the dependence of villus morphogenesis on endodermal topography. These investigations will be carried out in the chick, a model system that closely resembles human gastrointestinal development, and will rely on a combination of mechanically motivated physical manipulations and genetic ones to identify how developing tissues may exploit physical forces to position cells locally within spatially varying signaling gradients in order to specify their adult form. The proposed work may not only advance our knowledge of how gastrointestinal cancers form and can be treated, but may aid in understanding the fundamental mechanisms by which vertebrate morphogenesis proceeds through an integration of mechanical, molecular, and positional cues.