TY - JOUR
T1 - Renal defects associated with improper polarization of the CRB and DLG polarity complexes in MALS-3 knockout mice
AU - Olsen, Olav
AU - Funke, Lars
AU - Long, Jia Fu
AU - Fukata, Masaki
AU - Kazuta, Toshinari
AU - Trinidad, Jonathan C.
AU - Moore, Kimberly A.
AU - Misawa, Hidemi
AU - Welling, Paul A.
AU - Burlingame, Alma L.
AU - Zhang, Mingjie
AU - Bredt, David S.
PY - 2007/10/8
Y1 - 2007/10/8
N2 - 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.
AB - 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.
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U2 - 10.1083/jcb.200702054
DO - 10.1083/jcb.200702054
M3 - Article
C2 - 17923534
AN - SCOPUS:35349013107
SN - 0021-9525
VL - 179
SP - 151
EP - 164
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 1
ER -