The Hippo pathway, which controls tissue growth, and proteins that regulate apicobasal polarity have separately been implicated in renal cystogenesis. New research by Thomas Weide, Hermann Pavenstädt and colleagues shows that PALS1, a core apical polarity protein expressed in the human renal epithelium, mediates crosstalk between Hippo and TGF-β pathways and is involved in cyst formation.
To investigate the role of PALS1 in renal cystogenesis, the researchers generated mice with Pals1 haploinsufficient renal epithelial cells. These mice developed glomerular and tubular cysts, poor kidney perfusion and proteinuria, resulting in death within 6–8 weeks. In Pals1 haploinsufficent kidneys, the levels of YAP and TAZ, two transcriptional coactivators that are inhibited by the Hippo pathway, were strongly reduced, whereas target genes of the Hippo pathway (such as Ctgf, Birc2 and Cyr61) and markers of TGF-β activation, including biomarkers of renal disease, were strongly upregulated.
PALS1 ... is involved in cyst formation
In Drosophila nephrocytes, knockdown of the Pals1 ortholog Stardust induced malformation of slit-diaphragm-like structures and decreased uptake efficiency. These defects were rescued by knockdown of Yorkie, the Drosophila counterpart of YAP and TAZ. “The axis between cell polarity proteins and Hippo target proteins is conserved from fly to humans, which is of special interest as altered Hippo signalling in cyst-lining cells has previously been linked to renal cystic diseases,” says Weide.
The researchers also showed that PALS1 acts as an upstream regulator of the crosstalk between Hippo and TGF-β pathways in vitro. PALS1 knockdown in human and canine epithelial cell cultures caused partial inactivation of the Hippo pathway and hyperactivation of the response to TGF-β, including expression of Pai-1, a TGF-β target gene.
Weide, Pavenstädt and colleagues now plan to elucidate why partial reduction of PALS1 expression induces such a dramatic phenotype. “For that purpose, it will be interesting to investigate the physical and functional connections of PALS1 to other proteins and signalling pathways that have previously been linked to polycystic kidney disease or ciliopathies,” says Pavenstädt. “Next steps will involve establishing the PALS1 interactome in renal cells.”
Weide, T. et al. Pals1 haploinsufficiency results in proteinuria and cyst formation. J. Am. Soc. Nephrol. http://dx.doi.org/10.1681/ASN.2016040474 (2017)
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Aguilar, A. PALS1 links polarity, TGF-β and the Hippo pathway. Nat Rev Nephrol 13, 193 (2017). https://doi.org/10.1038/nrneph.2017.20