PUBLICATION
Leucine-Rich Repeat in Polycystin-1 Suppresses Cystogenesis in a Zebrafish (Danio rerio) Model of Autosomal-Dominant Polycystic Kidney Disease
- Authors
- Padhy, B., Amir, M., Xie, J., Huang, C.L.
- ID
- ZDB-PUB-240313-10
- Date
- 2024
- Source
- International Journal of Molecular Sciences 25(5): (Journal)
- Registered Authors
- Keywords
- laminin, leucine-rich repeats, polycystic kidney disease, polycystin-1 protein, zebrafish
- MeSH Terms
-
- TRPP Cation Channels/metabolism
- Humans
- Polycystic Kidney, Autosomal Dominant*/genetics
- Animals
- Leucine/metabolism
- Kidney/metabolism
- Polycystic Kidney Diseases*/metabolism
- Laminin/metabolism
- Zebrafish/genetics
- PubMed
- 38474131 Full text @ Int. J. Mol. Sci.
Citation
Padhy, B., Amir, M., Xie, J., Huang, C.L. (2024) Leucine-Rich Repeat in Polycystin-1 Suppresses Cystogenesis in a Zebrafish (Danio rerio) Model of Autosomal-Dominant Polycystic Kidney Disease. International Journal of Molecular Sciences. 25(5):.
Abstract
Mutations of PKD1 coding for polycystin-1 (PC1) account for most cases of autosomal-dominant polycystic kidney disease (ADPKD). The extracellular region of PC1 contains many evolutionarily conserved domains for ligand interactions. Among these are the leucine-rich repeats (LRRs) in the far N-terminus of PC1. Using zebrafish (Danio rerio) as an in vivo model system, we explored the role of LRRs in the function of PC1. Zebrafish expresses two human PKD1 paralogs, pkd1a and pkd1b. Knockdown of both genes in zebrafish by morpholino antisense oligonucleotides produced phenotypes of dorsal-axis curvature and pronephric cyst formation. We found that overexpression of LRRs suppressed both phenotypes in pkd1-morphant zebrafish. Purified recombinant LRR domain inhibited proliferation of HEK cells in culture and interacted with the heterotrimeric basement membrane protein laminin-511 (α5β1γ1) in vitro. Mutations of amino acid residues in LRRs structurally predicted to bind laminin-511 disrupted LRR-laminin interaction in vitro and neutralized the ability of LRRs to inhibit cell proliferation and cystogenesis. Our data support the hypothesis that the extracellular region of PC1 plays a role in modulating PC1 interaction with the extracellular matrix and contributes to cystogenesis of PC1 deficiency.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping