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Published online October 8, 2007
doi:10.1083/jcb.200702054
The Journal of Cell Biology, Vol. 179, No. 1, 151-164
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Olsen et al.
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Article

 Renal defects associated with improper polarization of the CRB and DLG polarity complexes in MALS-3 knockout mice

Olav Olsen1, Lars Funke1, Jia-fu Long4, Masaki Fukata1, Toshinari Kazuta1, Jonathan C. Trinidad3, Kimberly A. Moore2, Hidemi Misawa1, Paul A. Welling5, Alma L. Burlingame3, Mingjie Zhang4, and David S. Bredt1,6

1 Departments of Physiology, 2 Cellular and Molecular Pharmacology, and 3 Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143
4 Department of Biochemistry, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
5 Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201
6 Department of Integrative Biology, Eli Lilly and Company, Indianapolis, IN 46285

Correspondence to Olav Olsen: olav.olsen{at}ucsf.edu; or David S. Bredt: bredt{at}lilly.com

Kidney development and physiology require polarization of epithelia that line renal tubules. Genetic studies show that polarization of invertebrate epithelia requires the crumbs, partition-defective-3, and discs large complexes. These evolutionarily conserved protein complexes occur in mammalian kidney; however, their role in renal development remains poorly defined. Here, we find that mice lacking the small PDZ protein mammalian LIN-7c (MALS-3) have hypomorphic, cystic, and fibrotic kidneys. Proteomic analysis defines MALS-3 as the only known core component of both the crumbs and discs large cell polarity complexes. MALS-3 mediates stable assembly of the crumbs tight junction complex and the discs large basolateral complex, and these complexes are disrupted in renal epithelia from MALS-3 knockout mice. Interestingly, MALS-3 controls apico-basal polarity preferentially in epithelia derived from metanephric mesenchyme, and defects in kidney architecture owe solely to MALS expression in these epithelia. These studies demonstrate that defects in epithelial cell polarization can cause cystic and fibrotic renal disease.

O. Olsen and L. Funke contributed equally to this paper.

Abbreviations used in this paper: CRB, Crumbs; DLG, Discs large; LGL, lethal giant larvae; MAGUK, membrane-associated guanylate kinase; MALS-3, mammalian LIN-7c; MMKO, metanephric mesenchyme KO; PALS, proteins associated with LIN-7; PAR-3, partition-defective-3; PATJ, PALS-associated tight junction; SCRIB, scribble; UBKO, ureteric bud KO.


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