Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease

Abstract

BackgroundPKD1 or PKD2, the two main causal genes for autosomal dominant polycystic kidney disease (ADPKD), encode the multipass transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Polycystins localize to the primary cilium, an organelle essential for cell signaling, including signal transduction of the Hedgehog pathway. Mutations in ciliary genes that build and maintain the cilium also cause renal cystic disease through unknown pathways. Although recent studies have found alterations in Hedgehog signaling in ADPKD-related models and tissues, the relationship between Hedgehog and polycystic kidney disease is not known.MethodsTo examine the potential role of cell-autonomous Hedgehog signaling in regulating kidney cyst formation in vivo in both early- and adult-onset mouse models of ADPKD, we used conditional inactivation of Pkd1 combined with conditional modulation of Hedgehog signaling components in renal epithelial cells, where mutations in Pkd1 initiate cyst formation. After increasing or decreasing levels of Hedgehog signaling in cells that underwent inactivation of Pkd1, we evaluated the effects of these genetic manipulations on quantitative parameters of polycystic kidney disease severity.ResultsWe found that in Pkd1 conditional mutant mouse kidneys, neither downregulation nor activation of the Hedgehog pathway in epithelial cells along the nephron significantly influenced the severity of the polycystic kidney phenotype in mouse models of developmental or adult-onset of ADPKD.ConclusionsThese data suggest that loss of Pkd1 function results in kidney cysts through pathways that are not affected by the activity of the Hedgehog pathway.

Ciliopathy protein HYLS1 coordinates the biogenesis and signaling of primary cilia by activating the ciliary lipid kinase PIPKIγ

“…Although HYLS1 deficiency interrupted Gpr161 trafficking out of cilia, it did not affect polycystin-2, another ciliary membrane protein mutated in polycystic kidney disease (PKD). This is consistent with the lack of renal cysts in HLS1 fetuses ( 8 ) and the recent finding that cell-autonomous Hh signaling is dispensable for renal cyst progression in PKD mouse models ( 42 ).…”

Ttc30a affects tubulin modifications in a model for ciliary chondrodysplasia with polycystic kidney disease

“…In vitro analysis suggested that down-regulation of TTC30B had an inhibitory effect on Shh-pathway stimulation, consistent with our findings that Ttc30a has a role in limb patterning. Hh signaling does not influence cystogenesis in autosomal polycystic kidney disease, suggesting that other ciliary mechanisms are more likely to be at play ( 123 ). Further investigation will need to elucidate which signals are disrupted by loss of Ttc30a in renal cyst formation and which other molecular signals are affected by disrupted posttranslational tubulin modifications and defective ciliary compartmentalization.…”

CRISPR/Cas9 targeting Ttc30a mimics ciliary chondrodysplasia with polycystic kidney disease

“…In vitro analysis suggested that downregulation of TTC30B had an inhibitory effect on Shh-pathway stimulation, consistent with our findings that Ttc30a has a role in limb patterning. Hedgehog signalling does not influence cystogenesis in autosomal polycystic kidney disease (ADPKD), suggesting that other ciliary mechanisms are more likely to be at play 118 . Further investigation will need to elucidate, which signals are disrupted by loss of Ttc30a in renal cyst formation and to what degree polyglutamylation and - glycylation are more widely implicated in nephronophthisis and other ciliopathies.…”