Transporting epithelial cells build apical microvilli to increase membrane surface area and enhance absorptive capacity. The intestinal brush border provides an elaborate example with tightly packed microvilli that function in nutrient absorption and host defense. Although the brush border is essential for physiological homeostasis, its assembly is poorly understood. We found that brush border assembly is driven by the formation of Ca2+-dependent adhesion links between adjacent microvilli. Intermicrovillar links are composed of protocadherin-24 and mucin-like protocadherin, which target to microvillar tips and interact to form a trans-heterophilic complex. The cytoplasmic domains of microvillar protocadherins interact with the scaffolding protein, harmonin, and myosin-7b, which promote localization to microvillar tips. Finally, a mouse model of Usher syndrome lacking harmonin exhibits microvillar protocadherin mislocalization and severe defects in brush border morphology. These data reveal an adhesion-based mechanism for brush border assembly and illuminate the basis of intestinal pathology in patients with Usher syndrome. PaperFlick
Bibliographical noteFunding Information:
The authors thank all members of the M.J.T. laboratory and the Vanderbilt Epithelial Biology Center for advice and support. Electron and light microscopy was performed in part through the use of the VUMC Cell Imaging Shared Resource. This work was supported by Intramural Programs of NIDCD, NIH (to B.K.), American Heart Association (AHA) predoctoral fellowships (to D.A.S. and R.E.M.), AHA postdoctoral fellowship (to S.W.C.), AHA grant-in-aid 12GRNT12050314 (to M.J.T.), the VUMC Digestive Diseases Research Center (NIH P30DK058404), a Vanderbilt University IDEAS award (to M.J.T.), and NIH DC009246 (to Q.Y.Z.), DK075555, and DK095811 (to M.J.T.).
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)