Tulp3 Is a Ciliary Trafficking Gene that Regulates Polycystic Kidney Disease

Current Biology : CB
Emilie Legué, Karel F Liem

Abstract

The primary cilium is an organelle essential for cell signaling pathways. One of the most common human genetic diseases is autosomal dominant polycystic kidney disease (ADPKD), which is caused by mutations in the PKD1 or PKD2 genes that encode Polycystin 1 and 2 (PC1/2), transmembrane proteins that translocate to the cilium. Mutations in genes that disrupt ciliogenesis also cause kidney cysts as part of a "ciliopathic" disease spectrum. The molecular mechanisms that link cilia function with renal cystic diseases are not well understood, and the mechanistic relationship between ADPKD and ciliopathic PKD is not known. Here we identify the gene Tubby-like protein-3 (Tulp3) as a key regulator of renal cystic disease from a forward genetic screen in the mouse. Mice homozygous for a hypomorphic missense mutation within the conserved Tubby domain of Tulp3 develop cysts at late embryonic stages, leading to severe postnatal loss of kidney function. In contrast to other ciliopathic disease models, Tulp3 mutations do not affect ciliogenesis. Instead, we demonstrate that Tulp3 is essential for the trafficking of the Joubert syndrome-associated small GTPase Arl13b into kidney cilia. We show that reduction of Pkd1 dosage promotes cystogenesi...Continue Reading

Citations

Aug 28, 2019·Journal of the American Society of Nephrology : JASN·Ming MaKarel F Liem
Jun 2, 2020·Seminars in Cell & Developmental Biology·Ming Ma
Nov 15, 2020·The Journal of Biological Chemistry·Evan M KerekBasil P Hubbard
Jun 8, 2021·Frontiers in Cell and Developmental Biology·Wei WangPamela V Tran

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