title: 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 Ca(2+)-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:
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Crawley
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Shifrin
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Grega-Larson
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Russell E
authors.initials: RE
authors.lastname: McConnell
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Benesh
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Suli
authors.initials: S
authors.lastname: Mao
authors.affiliation: Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Qing Yin
authors.initials: QY
authors.lastname: Zheng
authors.affiliation: Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Ki Taek
authors.initials: KT
authors.lastname: Nam
authors.affiliation: National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Millis
authors.affiliation: National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Bechara
authors.initials: B
authors.lastname: Kachar
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: matthew.tyska@vanderbilt.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Tyska
mesh_terms: D000818:Animals; D019556:COS Cells; D018938:Caco-2 Cells; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D020895:Enterocytes / Q000166:cytology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008871:Microvilli / Q000378:metabolism* / Q000648:ultrastructure; D009218:Myosins / Q000378:metabolism; D052245:Usher Syndromes / Q000473:pathology
chemical_list: C464586:CDHR2 protein, human; C413024:CDHR5 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C492262:Ush1c protein, mouse; D009218:Myosins; D002118:Calcium
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