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

Area of Science:

• Genetics
• Developmental Biology
• Molecular Biology

Background:

• Mutations in polycystin1 (PKD1) cause most autosomal dominant polycystic kidney disease (ADPKD) cases.
• PKD1 mutations are linked to vascular and abdominal wall defects, suggesting polycystin1's role in extracellular matrix (ECM) integrity.

Purpose of the Study:

• To investigate the role of polycystins (PKD1 paralogs pkd1a/b and PKD2) in axial morphogenesis and ECM regulation in zebrafish.
• To elucidate the molecular mechanisms by which polycystins influence collagen gene expression and ECM assembly.

Main Methods:

• Zebrafish knockdown models for pkd1a/b and pkd2.
• Analysis of axial development, craniofacial structures, and pronephric cysts.
• Assessment of collagen gene expression (col2a1) and collagen crosslinking.
• Pharmacological inhibition of collagen crosslinking and PI3K signaling.

Main Results:

• Combined knockdown of pkd1a/b and pkd2 caused dorsal axis curvature, hydrocephalus, and craniofacial defects, interacting in axial development.
• Axis defects were linked to notochord collagen overexpression, reversible by col2a1 knockdown or collagen crosslinking inhibition.
• pkd1a/b and pkd2 deficiency led to ectopic collagen mRNA expression, indicating a loss of negative feedback.
• Polycystin knockdown sensitized embryos to collagen crosslinking inhibitors, and PI3K inhibition dysregulated col2a1 expression.

Conclusions:

• pkd1a/b and pkd2 interact to regulate ECM secretion and assembly, potentially through a PI3K-dependent negative feedback pathway.
• Altered ECM integrity due to polycystin dysfunction may be a primary defect in ADPKD.
• These findings highlight a novel role for polycystins in matrix homeostasis relevant to ADPKD pathogenesis.