Tuft Luck: Polycystin-1's Role in Intestinal Epithelial Remodeling

Gut barrier disruption has been recognized as a symptom in patients with polycystic kidney disease, but what causes this affliction is not entirely known. This project examines how dysfunction of polycystin-1 (PC1), encoded by PKD1, influences epithelial cell fate and promotes tuft cell expansion. Using inducible mouse models, we show that loss of PC1 leads to a significant increase in tuft cell abundance, suggesting that PC1 normally functions to restrain differentiation toward this lineage. Importantly, we find that tuft cell hyperplasia actually precedes cystogenesis. These findings point to a role for PC1 in maintaining epithelial homeostasis by limiting activation of differentiation programs associated with inflammation. Additionally, treatment with β-hydroxybutyrate (BHB), a ketone body with known signaling functions, significantly attenuates tuft cell hyperplasia in murine models of PKD, highlighting a potential link between metabolic signaling and epithelial differentiation.