Pals1 Haploinsufficiency Results in Proteinuria and Cyst Formation.
The nephron is the basic physiologic subunit of the mammalian kidney and is made up of several apicobasally polarized epithelial cell types. The process of apicobasal polarization in animal cells is controlled by the evolutionarily conserved Crumbs (CRB), Partitioning-defective, and Scribble protein complexes. Here, we investigated the role of protein associated with LIN-7 1 (Pals1, also known as Mpp5), a core component of the apical membrane-determining CRB complex in the nephron. Pals1 interacting proteins, including Crb3 and Wwtr1/Taz, have been linked to renal cyst formation in mice before. Immunohistologic analysis revealed Pals1 expression in renal tubular cells and podocytes of human kidneys. Mice lacking one Pals1 allele (functionally haploid for Pals1) in nephrons developed a fully penetrant phenotype, characterized by cyst formation and severe defects in renal barrier function, which led to death within 6-8 weeks. InDrosophilanephrocytes, deficiency of the Pals1 ortholog caused alterations in slit-diaphragm-like structures. Additional studies in epithelial cell culture models revealed that Pals1 functions as a dose-dependent upstream regulator of the crosstalk between Hippo- and TGF-β-mediated signaling. Furthermore, Pals1 haploinsufficiency in mouse kidneys associated with the upregulation of Hippo pathway target genes and marker genes of TGF-βsignaling, including biomarkers of renal diseases. These findings support a link between apical polarity proteins and renal diseases, especially renal cyst diseases. Further investigation of the Pals1-linked networks is required to decipher the mechanisms underlying the pathogenesis of these diseases.
Internal Medicine D, University Hospital of Münster, Münster, Germany; hermann.pavenstaedt@ukmuenster.de weidet@uni-muenster.de.
Thomas
T
Weide
Internal Medicine D, University Hospital of Münster, Münster, Germany.
Beate
B
Vollenbröker
Internal Medicine D, University Hospital of Münster, Münster, Germany.
Ulf
U
Schulze
Internal Medicine D, University Hospital of Münster, Münster, Germany.
Ivona
I
Djuric
Internal Medicine D, University Hospital of Münster, Münster, Germany.
Maria
M
Edeling
Internal Medicine D, University Hospital of Münster, Münster, Germany.
Jakob
J
Bonse
Institute for Molecular and Cellular Anatomy, University of Regensburg, Regensburg, Germany.
Florian
F
Hochapfel
Institute for Molecular and Cellular Anatomy, University of Regensburg, Regensburg, Germany.
Olga
O
Panichkina
Internal Medicine D, University Hospital of Münster, Münster, Germany.
Dirk-Oliver
DO
Wennmann
Internal Medicine D, University Hospital of Münster, Münster, Germany.
Britta
B
George
Shriners Hospitals Pediatric Research Center, Department of Anatomy and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.
Seonhee
S
Kim
Nephropathology Department, Institute of Pathology, Erlangen-Nürnberg University, Erlangen, Germany.
Christoph
C
Daniel
Interdisciplinary Center for Clinical Research, University of Münster, Munster, Germany; and.
Jochen
J
Seggewiß
Nephropathology Department, Institute of Pathology, Erlangen-Nürnberg University, Erlangen, Germany.
Kerstin
K
Amann
Department of Neuroanatomy, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Wilhelm
W
Kriz
Institute for Molecular and Cellular Anatomy, University of Regensburg, Regensburg, Germany.
Michael P
MP
Krahn
Internal Medicine D, University Hospital of Münster, Münster, Germany; hermann.pavenstaedt@ukmuenster.de weidet@uni-muenster.de.
Hermann
H
Pavenstädt
D000818:Animals; D004330:Drosophila; D005260:Female; D057895:Haploinsufficiency; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009703:Nucleoside-Phosphate Kinase / Q000235:genetics*; D011507:Proteinuria / Q000235:genetics*
D008565:Membrane Proteins; D009703:Nucleoside-Phosphate Kinase; C499979:Mpp5 protein, mouse
Mpp5; Pals1; cell polarity; cell signaling; cystic kidney; proteinuria