Renal defects associated with improper polarization of the CRB and DLG polarity complexes in MALS-3 knockout mice.
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.
Olsen
Olav
O
Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA. olav.olsen@ucsf.edu
Funke
Lars
L
Long
Jia-fu
JF
Fukata
Masaki
M
Kazuta
Toshinari
T
Trinidad
Jonathan C
JC
Moore
Kimberly A
KA
Misawa
Hidemi
H
Welling
Paul A
PA
Burlingame
Alma L
AL
Zhang
Mingjie
M
Bredt
David S
DS
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism / Q000502:physiology; D018797:Cell Cycle Proteins; D004847:Epithelial Cells / Q000378:metabolism; D007668:Kidney / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology; D038081:Organogenesis / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D019108:Tight Junctions / Q000378:metabolism / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; C453730:Crb1 protein, mouse; C114672:Lin7c protein, mouse; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; C115084:Pard3 protein, mouse; D021122:Protein Subunits