Mathew Sijo, Palamuttam Riya J, Mernaugh Glenda, Ramalingam Harini, Lu Zhenwei, Zhang Ming-Zhi, Ishibe Shuta, Critchley David R, Fässler Reinhard, Pozzi Ambra, Sanders Charles R, Carroll Thomas J, Zent Roy
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Department of Medicine and Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Development. 2017 Nov 15;144(22):4148-4158. doi: 10.1242/dev.149914. Epub 2017 Oct 9.
Kidney collecting system development requires integrin-dependent cell-extracellular matrix interactions. Integrins are heterodimeric transmembrane receptors consisting of α and β subunits; crucial integrins in the kidney collecting system express the β1 subunit. The β1 cytoplasmic tail has two NPxY motifs that mediate functions by binding to cytoplasmic signaling and scaffolding molecules. Talins, scaffolding proteins that bind to the membrane proximal NPxY motif, are proposed to activate integrins and to link them to the actin cytoskeleton. We have defined the role of talin binding to the β1 proximal NPxY motif in the developing kidney collecting system in mice that selectively express a Y-to-A mutation in this motif. The mice developed a hypoplastic dysplastic collecting system. Collecting duct cells expressing this mutation had moderate abnormalities in cell adhesion, migration, proliferation and growth factor-dependent signaling. In contrast, mice lacking talins in the developing ureteric bud developed kidney agenesis and collecting duct cells had severe cytoskeletal, adhesion and polarity defects. Thus, talins are essential for kidney collecting duct development through mechanisms that extend beyond those requiring binding to the β1 integrin subunit NPxY motif.
肾集合系统的发育需要整合素依赖的细胞与细胞外基质的相互作用。整合素是由α和β亚基组成的异二聚体跨膜受体；肾集合系统中的关键整合素表达β1亚基。β1胞质尾部有两个NPxY基序，通过与胞质信号和支架分子结合来介导功能。踝蛋白是与膜近端NPxY基序结合的支架蛋白，被认为可激活整合素并将其与肌动蛋白细胞骨架相连。我们已经确定了在小鼠发育中的肾集合系统中，踝蛋白与β1近端NPxY基序结合的作用，这些小鼠在该基序中选择性地表达Y到A的突变。这些小鼠发育出发育不全的发育异常的集合系统。表达这种突变的集合管细胞在细胞黏附、迁移、增殖和生长因子依赖性信号传导方面有中度异常。相比之下，在发育中的输尿管芽中缺乏踝蛋白的小鼠发生肾缺如，集合管细胞有严重的细胞骨架、黏附和极性缺陷。因此，踝蛋白对于肾集合管的发育至关重要，其作用机制超出了那些需要与β1整合素亚基NPxY基序结合的机制。
