Talin regulates integrin β1 dependent and independent cell functions in ureteric bud development

Author:

Mathew Sijo1,Palamuttam Riya J.1,Mernaugh Glenda1,Ramalingam Harini2,Lu Zhenwei34,Zhang Ming-Zhi1,Ishibe Shuta5,Critchley David R.6,Fässler Reinhard7,Pozzi Ambra148,Sanders Charles R.93ORCID,Carroll Thomas J.2,Zent Roy1108ORCID

Affiliation:

1. Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, USA

2. Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390,USA

3. Center for Structure Biology, Vanderbilt University Medical Center, Nashville, USA

4. Department of Molecular Physiology, Vanderbilt University Medical Center, Nashville, USA

5. Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

6. Department of Biochemistry, University of Leicester, United Kingdom

7. Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany

8. Veteran Affairs Hospital Nashville, USA

9. Department of Biochemistry, Vanderbilt University Medical Center, Nashville, USA

10. Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, USA

Abstract

Kidney collecting system development requires integrin-dependent cell-extracellular matrix interactions. Integrins, are heterodimeric transmembrane receptors consisting of α and β subunits and critical integrins in the kidney collecting system express the β1subunit. 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 link them to the actin cytoskeleton. We 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.

Funder

National Institute of Diabetes and Digestive and Kidney Diseases

American Heart Association

U.S. Department of Veterans Affairs

Publisher

The Company of Biologists

Subject

Developmental Biology,Molecular Biology

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