Primary cilium regulates CaV1.2 expression through Wnt signaling.
Primary cilia are sensory organelles that provide a feedback mechanism to restrict Wnt signaling in the absence of endogenous Wnt activators. Abnormal Wnt signaling has been shown to result in polycystic kidney disease (PKD) although the exact mechanism has been debated. Previously, we reported that the calcium channel CaV1.2 functions in primary cilia. In this study, we show that CaV1.2 expression level is regulated by Wnt signaling. This occurs through modulation of mitochondrial mass and activity resulting in increased reactive oxygen species which generate oxidative DNA lesions. We found that the subsequent cellular DNA damage response triggers increased CaV1.2 expression. In the absence of primary cilia where Wnt signaling is upregulated, we found that CaV1.2 is overexpressed as a compensatory mechanism. We show for the first time that CaV1.2 knockdown in zebrafish results in classic primary cilia defects including renal cyst formation, hydrocephalus, and left-right asymmetry defects. Our study shows that suppressed Wnt signaling prevents CaV1.2 expression ultimately resulting in PKD phenotypes. Thus, CaV1.2 expression is tightly regulated through Wnt signaling and plays an essential sensory role in primary cilia necessary for cellular homeostasis.
Department of Medicinal and Biological Chemistry, The University of Toledo, Toledo, Ohio.
Brian S
BS
Muntean
Xingjian
X
Jin
Frederick E
FE
Williams
Surya M
SM
Nauli
D000818:Animals; D020746:Calcium Channels, L-Type / Q000096:biosynthesis* / Q000235:genetics; D002923:Cilia / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007690:Polycystic Kidney Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics*; D015027:Zebrafish
D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D017382:Reactive Oxygen Species