Intestinal brush border assembly driven by protocadherin-based intermicrovillar adhesion

Scott W. Crawley; David A. Shifrin; Nathan E. Grega-Larson; Russell E. McConnell; Andrew E. Benesh; Suli Mao; Yuxi Zheng; Qing Yin Zheng; Ki Taek Nam; Bryan A. Millis; Bechara Kachar; Matthew J. Tyska

doi:10.1016/j.cell.2014.01.067

Intestinal brush border assembly driven by protocadherin-based intermicrovillar adhesion

Scott W. Crawley, David A. Shifrin, Nathan E. Grega-Larson, Russell E. McConnell, Andrew E. Benesh, Suli Mao, Yuxi Zheng, Qing Yin Zheng, Ki Taek Nam, Bryan A. Millis, Bechara Kachar, Matthew J. Tyska

BioMedical Science Institute

Research output: Contribution to journal › Article › peer-review

121 Citations (Scopus)

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 patients with Usher syndrome. PaperFlick

Original language	English
Pages (from-to)	433-446
Number of pages	14
Journal	Cell
Volume	157
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2014.01.067
Publication status	Published - 2014 Apr 10

Bibliographical note

Funding 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)

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10.1016/j.cell.2014.01.067

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@article{917bdec6888f477fad44889a7fbfe6e2,

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 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",

author = "Crawley, {Scott W.} and Shifrin, {David A.} and Grega-Larson, {Nathan E.} and McConnell, {Russell E.} and Benesh, {Andrew E.} and Suli Mao and Yuxi Zheng and Zheng, {Qing Yin} and Nam, {Ki Taek} and Millis, {Bryan A.} and Bechara Kachar and Tyska, {Matthew J.}",

note = "Funding 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.). ",

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language = "English",

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AU - Crawley, Scott W.

AU - Shifrin, David A.

AU - Grega-Larson, Nathan E.

AU - McConnell, Russell E.

AU - Benesh, Andrew E.

AU - Mao, Suli

AU - Zheng, Yuxi

AU - Zheng, Qing Yin

AU - Nam, Ki Taek

AU - Millis, Bryan A.

AU - Kachar, Bechara

AU - Tyska, Matthew J.

N1 - Funding 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.).

PY - 2014/4/10

Y1 - 2014/4/10

N2 - 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

AB - 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

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JO - Cell

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Intestinal brush border assembly driven by protocadherin-based intermicrovillar adhesion

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

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