A novel Ezrin-dependent cell division drives villus formation

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): The structural design of the intestine reflects its critical function in the absorption of nutrients from food: its enormous absorptive surface area is augmented by regular folding of the epithelium into finger-like projections called villi. These vili, with their mesenchymally derived vascular cores covered by a single layer of epithelium, represent the minimal functional units of the intestine. In mice, villus development is initiated a embryonic day (E)14.5, when the thick pseudostratified epithelium with a flat luminal surface is converted to a columnar epithelium covering a regularly patterned field of emerging villi. This dramatic remodeling generates a tremendous increase in luminal absorptive surface area and is accompanied by complex changes in epithelial cell polarity, proliferation, and shape. Classical morphological studies have suggested that this remodeling requires de novo formation of secondary lumina, which then fuse with the primary lumen to carve out villi. In mice deficient in ezrin, an apical surface protein, fused villi are observed throughout the intestine; this was previously interpreted as incomplete secondary lumen coalescence. However, new findings indicate that luminal extension takes place from the main lumen outward, rather than by formation of secondary lumina. To accomplish this, a novel form of cell division in proposed, in which apical determinants are deposited at the cytokinetic plane of the mitotic cell, effectively separating the daughter cells onto two different developing villi and simultaneously expanding the apical surface. This specialized cell division is called an e-division (for lumen extending division). The hypothesis driving this work is that Ezrin facilitates complete separation of daughters during e-division; its loss results in sporadically fused villi. This makes three predictions: a) that ezrin function will be important only at E14.5-E15.5, when e-divisions are occurring; b) that cellular bridges in Ez-/- mice will be derived from incomplete e-divisions; and c) that the first division of isolated intestinal stem cells in organoid culture is functionally equivalent to an e-division and can be used to model these divisions and further dissect their molecular pathways. All three predictions will be experimentally tested. Elucidation of the cellular and molecular processes that control e-divisions will lead to a better understanding of the process of villus morphogenesis, information that, in turn, will have important implications fo the bioengineering of fetal intestinal tissue and the treatment of intestinal failure.