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The ADPKD genes pkd1a/b and pkd2 regulate extracellular matrix formation.

Mutations in polycystin1 (PKD1) account for the majority of autosomal dominant polycystic kidney disease (ADPKD). PKD1 mutations are also associated with vascular aneurysm and abdominal wall hernia, suggesting a role for polycystin1 in extracellular matrix (ECM) integrity. In zebrafish, combined knockdown of the PKD1 paralogs pkd1a and pkd1b resulted in dorsal axis curvature, hydrocephalus, cartilage and craniofacial defects, and pronephric cyst formation at low frequency (10-15%). Dorsal axis curvature was identical to the axis defects observed in pkd2 knockdown embryos. Combined pkd1a/b, pkd2 knockdown demonstrated that these genes interact in axial morphogenesis. Dorsal axis curvature was linked to notochord collagen overexpression and could be reversed by knockdown of col2a1 mRNA or chemical inhibition of collagen crosslinking. pkd1a/b- and pkd2-deficient embryos exhibited ectopic, persistent expression of multiple collagen mRNAs, suggesting a loss of negative feedback signaling that normally limits collagen gene expression. Knockdown of pkd1a/b also dramatically sensitized embryos to low doses of collagen-crosslinking inhibitors, implicating polycystins directly in the modulation of collagen expression or assembly. Embryos treated with wortmannin or LY-29400 also exhibited dysregulation of col2a1 expression, implicating phosphoinositide 3-kinase (PI3K) in the negative feedback signaling pathway controlling matrix gene expression. Our results suggest that pkd1a/b and pkd2 interact to regulate ECM secretion or assembly, and that altered matrix integrity may be a primary defect underlying ADPKD tissue pathologies.

Pubmed ID: 20335443


  • Mangos S
  • Lam PY
  • Zhao A
  • Liu Y
  • Mudumana S
  • Vasilyev A
  • Liu A
  • Drummond IA


Disease models & mechanisms

Publication Data

April 29, 2010

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK53093
  • Agency: NIDDK NIH HHS, Id: DK54711
  • Agency: NIDDK NIH HHS, Id: K08 DK082782
  • Agency: NIDDK NIH HHS, Id: R01 DK070263

Mesh Terms

  • Body Patterning
  • Calcium
  • Chondrogenesis
  • Cloning, Molecular
  • Collagen
  • Craniofacial Abnormalities
  • Cross-Linking Reagents
  • Endoplasmic Reticulum
  • Extracellular Matrix
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Humans
  • Kidney
  • Models, Biological
  • Phosphatidylinositol 3-Kinases
  • Polycystic Kidney, Autosomal Dominant
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • TRPP Cation Channels