Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH 44106, USA.
Cell. 2014 Apr 10;157(2):433-446. doi: 10.1016/j.cell.2014.01.067.
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:
转运上皮细胞构建顶端微绒毛以增加膜表面积并增强吸收能力。肠道刷状缘提供了一个精细的例子，其紧密排列的微绒毛在营养吸收和宿主防御中发挥作用。尽管刷状缘对于生理内稳态至关重要，但对其组装过程了解甚少。我们发现，刷状缘的组装是由相邻微绒毛之间形成的 Ca(2+)依赖性黏附连接驱动的。微绒毛间的连接由原钙黏蛋白-24 和黏蛋白样原钙黏蛋白组成，它们靶向微绒毛尖端并相互作用形成跨异嗜性复合物。微绒毛原钙黏蛋白的细胞质结构域与支架蛋白 harmonin 和肌球蛋白-7b 相互作用，促进其定位到微绒毛尖端。最后，缺乏 harmonin 的 Usher 综合征小鼠模型表现出微绒毛原钙黏蛋白定位错误和刷状缘形态严重缺陷。这些数据揭示了刷状缘组装的黏附基础机制，并阐明了 Usher 综合征患者肠道病理学的基础。
