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Free keywords:
COLLECTING-DUCT DEVELOPMENT; NPXY MOTIFS; ACTIVATION; KIDNEY;
BETA-1-INTEGRIN; MAINTENANCE; BINDING; DOMAIN; HEAD; MICEDevelopmental Biology; Kidney; Signaling; Nuclear magnetic resonance; Tubules;
Abstract:
Kidney collecting system development requires integrin-dependent cell-extracellular matrix interactions. Integrins are heterodimeric transmembrane receptors consisting of alpha and beta subunits; crucial integrins in the kidney collecting systemexpress the beta 1 subunit. The beta 1 cytoplasmic tail has two NPxYmotifs 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 beta 1 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 beta 1 integrin subunit NPxY motif.
