PUBLICATION

Control of the Wnt pathways by nephrocystin-4 is required for morphogenesis of the zebrafish pronephros

Authors
Burcklé, C., Gaudé, H.M., Vesque, C., Silbermann, F., Salomon, R., Jeanpierre, C., Antignac, C., Saunier, S., and Schneider-Maunoury, S.
ID
ZDB-PUB-110518-11
Date
2011
Source
Human molecular genetics   20(13): 2611-27 (Journal)
Registered Authors
Schneider-Maunoury, Sylvie
Keywords
none
MeSH Terms
  • Phosphoproteins/metabolism
  • beta Catenin/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Adaptor Proteins, Signal Transducing/metabolism
  • Cilia/genetics
  • Cilia/pathology
  • Protein Transport/genetics
  • Mitosis/genetics
  • Zebrafish/embryology*
  • Zebrafish/genetics*
  • HEK293 Cells
  • Dogs
  • Apoptosis/genetics
  • Wnt Proteins/metabolism*
  • Protein Stability
  • Humans
  • Cell Line
  • Protein Binding/genetics
  • Animals, Genetically Modified
  • Animals
  • Phenotype
  • Morphogenesis/genetics*
  • Signal Transduction/genetics*
(all 24)
PubMed
21498478 Full text @ Hum. Mol. Genet.
Abstract
Nephronophthisis is a hereditary nephropathy characterized by interstitial fibrosis and cyst formation. It is caused by mutations in NPHP genes encoding the ciliary proteins, nephrocystins. In this paper, we investigate the function of nephrocystin-4, the product of the nphp4 gene, in vivo by morpholino-mediated knockdown in zebrafish and in vitro in mammalian kidney cells. Depletion of nephrocystin-4 results in convergence and extension defects, impaired laterality, retinal anomalies and pronephric cysts associated with alterations in early cloacal morphogenesis. These defects are accompanied by abnormal ciliogenesis in the cloaca and in the laterality organ. We show that nephrocystin-4 is required for the elongation of the caudal pronephric primordium and for the regulation of cell rearrangements during cloaca morphogenesis. Moreover, depletion of either inversin, the product of the nphp2 gene, or of the Wnt-planar cell polarity (PCP) pathway component prickle2 increases the proportion of cyst formation in nphp4-depleted embryos. Nephrocystin-4 represses the Wnt-β-catenin pathway in the zebrafish cloaca and in mammalian kidney cells in culture. In these cells, nephrocystin-4 interacts with inversin and dishevelled, and regulates dishevelled stability and subcellular localization. Our data point to a function of nephrocystin-4 in a tight regulation of the Wnt-²-catenin and Wnt-PCP pathways, in particular during morphogenesis of the zebrafish pronephros. Moreover, they highlight common signalling functions for inversin and nephrocystin-4, suggesting that these two nephrocystins are involved in common physiopathological mechanisms.
Genes / Markers
Figures
No images available
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
WT + MO1-nphp4standard conditions5-9 somites
WT + MO1-nphp4standard conditions5-9 somites
WT + MO1-nphp4standard conditions10-13 somites
WT + MO1-nphp4standard conditions10-13 somites
WT + MO1-nphp4standard conditions10-13 somites to 14-19 somites
WT + MO1-nphp4standard conditionsPrim-5
WT + MO1-nphp4standard conditionsPrim-5
WT + MO1-nphp4standard conditionsPrim-5
WT + MO1-nphp4standard conditionsPec-fin
WT + MO1-nphp4standard conditionsPec-fin
1 - 10 of 51
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
m209
    		Point Mutation
    w25TgTransgenic Insertion
      zf106TgTransgenic Insertion
        1 - 3 of 3
        Show
        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        invsMO2-invsMRPHLNO
        nphp4MO1-nphp4MRPHLNO
        nphp4MO2-nphp4MRPHLNO
        prickle1aMO1-prickle1aMRPHLNO
        prickle2bMO1-prickle2bMRPHLNO
        scribMO1-scribMRPHLNO
        vangl2MO1-vangl2MRPHLNO
        1 - 7 of 7
        Show
        Fish
        Fish
        vangl2m209/m209
        vangl2m209/m209 + MO1-nphp4
        w25Tg
        WT
        WT + MO1-nphp4
        WT + MO1-nphp4 + MO1-prickle1a
        WT + MO1-nphp4 + MO1-prickle2b
        WT + MO1-nphp4 + MO1-scrib
        WT + MO1-nphp4 + MO1-vangl2
        WT + MO1-prickle1a
        1 - 10 of 18
        Show
        Antibodies
        Orthology
        Engineered Foreign Genes
        Marker Marker Type Name
        EGFPEFGEGFP
        GFPEFGGFP
        1 - 2 of 2
        Show
        Mapping
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        Citation
        Burcklé, C., Gaudé, H.M., Vesque, C., Silbermann, F., Salomon, R., Jeanpierre, C., Antignac, C., Saunier, S., and Schneider-Maunoury, S. (2011) Control of the Wnt pathways by nephrocystin-4 is required for morphogenesis of the zebrafish pronephros. Human molecular genetics. 20(13):2611-27.