Intestinal Brush Border Assembly Driven by Protocadherin-Based Intermicrovillar Adhesion

Abstract

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 Usher syndrome patients.

Structure of Myo7b/USH1C complex suggests a general PDZ domain binding mode by MyTH4-FERM myosins

“…The Myo7b NMF binds to the central region of ANKS4B, which shares high homology with USH1G with a similar structural mechanism as the Myo7a/USH1G interaction (25, 26). The C-terminal MyTH4-FERM tandem (CMF) of Myo7b has been shown to bind to the C-terminal PDZ domains of USH1C (10,25,26). The direct binding of USH1C PDZ domains to Myo7b CMF is highly unexpected, as Myo7b CMF does not contain any recognizable C-terminal or internal PDZ-binding motif (PBM) (27).…”

Listen to your gut: Using adhesion to shape the surface of functionally diverse epithelia

“…However, recent discoveries implicate cadherin superfamily members in this process. We now know that microvilli are organized during brush border assembly by adhesion complexes that form between the tips of adjacent protrusions 14 (Fig. 1B).…”

“…In support of this assertion, mice lacking USH1C (a model for human Type 1C Usher syndrome) exhibit significant defects in microvillar packing along the length of the small intestine and colon. 14 Because several forms of Type 1 Usher syndrome (USH1E, USH1H, and USH1K) have yet to be assigned to a specific gene, future studies might reveal additional IMAC components. Parallels between the IMAC and tip-link complex have also allowed exploration of how specific mutations lead to disease in Usher syndrome patients.…”

“…14 Cytoplasmic binding partners might also be involved in positioning the IMAC at the distal tips, as a variant of CDHR2 lacking the cytoplasmic tail is unable to enrich in these sites. 14 Other actin-based protrusions that accumulate specific factors at their tips have invoked myosin motors to drive transport to and enrichment at the barbed-ends of supporting actin bundles (e.g., myosin-10 in filopodia). [16][17][18][19][20][21] A myosin motor might play a similar role in microvilli as the cytoplasmic domains of CDHR2 and CDHR5 interact with the tandem MyTH4/FERM (MF) domain motor, myosin-7b (MYO7B).…”

La dysplasie épithéliale intestinale, ou quand l’intestin est sous « deux de tension » cellulaire

“…La monocouche de cellules épithéliales qui tapisse l'intestin grêle présente une architecture simple et régulière, où les cellules prolifératives et les cellules différenciées sont distribuées dans des compartiments tissulaires différents : respectivement, les « cryptes » et les « villosités ». Tandis que les entérocytes évoluent le long de la villosité, les cellules suivent un processus d'organisation spécifique, appelé différenciation terminale, avec la formation d'une structure fonctionnelle au cortex apical, la bordure en brosse des microvillosités ; celle-ci expose les enzymes intestinales, augmente la surface membranaire au pôle apical et potentialise ainsi l'absorption de nutriments à l'interface entre la lumière de l'intestin et l'épithélium [1,2].…”