Kindlins regulate integrin- and growth factor-dependent ureteric bud formation

Area of Science:

• Developmental Biology
• Cell Biology
• Molecular Biology

Background:

• Kidney collecting system development relies on ureteric bud (UB) branching.
• This process involves extracellular matrix interactions with β1-integrin receptors.
• Integrin binding affinity is modulated by kindlins, which interact with the β subunit tail.

Purpose of the Study:

• To investigate the role of kindlins in regulating β1-integrin function during kidney development.
• To elucidate the specific contributions of kindlin-mediated integrin binding to UB branching and collecting duct (CD) formation.

Main Methods:

• Generation of mice with mutated β1-integrins lacking kindlin binding sites in the UB.
• Analysis of kidney development and CD cell function in these mice.
• Generation and analysis of kindlin-knockout mice and CD cells.

Main Results:

• Mice with kindlin-binding deficient β1-integrins showed medullary hypoplasia and moderate branching defects.
• Mutant CD cells exhibited impaired tubulogenesis, spreading, and adhesion but retained growth factor signaling.
• Kindlin-knockout mice were anephric, indicating a complete failure of UB budding.
• Kindlin-knockout CD cells failed to spread, adhere, or respond to growth factors, even with ligand-bound integrins.

Conclusions:

• Kindlins regulate both integrin function and critical growth factor signaling pathways.
• Kindlins are essential for initial ureteric bud formation and subsequent kidney development.
• Distinct roles for kindlin-binding integrins versus kindlin proteins themselves in kidney development.