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First published online 30 May 2007
doi: 10.1242/dev.005033

Development 134, 2501-2509 (2007)
Published by The Company of Biologists 2007
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The ECM protein nephronectin promotes kidney development via integrin {alpha}8ß1-mediated stimulation of Gdnf expression

James M. Linton1, Gail R. Martin2 and Louis F. Reichardt1,3,*

1 Department of Physiology, 1550 Fourth Street, University of California, San Francisco, San Francisco, CA 94143, USA.
2 Department of Anatomy and 1550 Fourth Street, University of California, San Francisco, San Francisco, CA 94143, USA.
3 Howard Hughes Medical Institute, 1550 Fourth Street, University of California, San Francisco, San Francisco, CA 94143, USA.

* Author for correspondence (e-mail: lfr{at}cgl.ucsf.edu)

Accepted 2 May 2007

Development of the metanephric kidney crucially depends on proper interactions between cells and the surrounding extracellular matrix. For example, we showed previously that in the absence of {alpha}8ß1 integrin, invasion by the ureteric bud into the metanephric mesenchyme is inhibited, resulting in renal agenesis. Here we present genetic evidence that the extracellular matrix protein nephronectin is an essential ligand that engages {alpha}8ß1 integrin during early kidney development. We show that embryos lacking a functional nephronectin gene frequently display kidney agenesis or hypoplasia, which can be traced to a delay in the invasion of the metanephric mesenchyme by the ureteric bud at an early stage of kidney development. Significantly, we detected no defects in extracellular matrix organization in the nascent kidneys of the nephronectin mutants. Instead, we found that Gdnf expression was dramatically reduced in both nephronectin- and {alpha}8 integrin-null mutants specifically in the metanephric mesenchyme at the time of ureteric bud invasion. We show that this reduction is sufficient to explain the agenesis and hypoplasia observed in both mutants. Interestingly, the reduction in Gdnf expression is transient, and its resumption presumably enables the nephronectin-deficient ureteric buds to invade the metanephric mesenchyme and begin branching. Our results thus place nephronectin and {alpha}8ß1 integrin in a pathway that regulates Gdnf expression and is essential for kidney development.

Key words: Kidney, Integrin, Extracellular matrix, GDNF, Mouse, Ureteric bud


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Development 2007 134: e1305. [Full Text]  





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