Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy

Abstract

Bardet-Biedl syndrome (BBS) is a multisystemic disorder typified by developmental and progressive degenerative defects. A combination of genetic, in vitro, and in vivo studies have highlighted ciliary dysfunction as a primary cause of BBS pathology, which has in turn contributed to the improved understanding of the functions of the primary cilium in humans and other vertebrates. Here we discuss the evidence linking the clinical BBS phenotype to ciliary defects, highlight how the genetic and cellular characteristics of BBS overlap with and inform other ciliary disorders, and explore the possible mechanistic underpinnings of ciliary dysfunction.

Figure 1. Contribution of each BBS gene to total mutational load.

Graph of the percentage contribution of each known BBS gene to BBS cases. Modified and updated from Human Molecular Genetics (14).

Figure 2. Signaling pathways in the cilium.

(A) Hedgehog signaling is regulated by the Ptch1 and Smo receptors. Binding of the hedgehog ligand to Ptch1 alleviates its inhibition of transport of Smo into the cilium, where it may regulate IFT involvement in Gli processing to either its activator form (Gli^A) or repressor form (Gli^R). Downstream targets of Gli-directed transcription include limb/digit formation, neurogenesis, and neural development. (B) Canonical and noncanonical Wnt signaling components are associated with the cilium and basal body. Binding of a canonical Wnt ligand to Frizzled (Fz) and LPL-related protein (Lrp) receptors causes Dishevelled-mediated (Dvl-mediated) recruitment of the β-catenin destruction complex to the plasma membrane, preventing β-catenin degradation. β-Catenin can then regulate T cell factor– and lymphoid-enhanced binding factor–mediated (TCF- and LEF-mediated) transcription of targets in the nucleus and subsequent processes such as cell proliferation and specification of cell fates. In the absence of ligand, Dvl and the β-catenin destruction complex exist freely in the cytoplasm and can target β-catenin for proteasome-mediated degradation. BBS proteins regulate proteasome function in addition to the transport of Inversin (Inv) from the basal body into the cytoplasm, where it can reduce cytoplasmic levels of Dvl via phosphorylation, a process that can also be regulated by Kif3a. Binding of a noncanonical Wnt ligand also recruits Dvl to the Fz receptor, a process regulated by Inv. This initiates activation of downstream targets, including the PCP effectors RhoA and JNK, and downstream processes that affect the actin cytoskeleton, cell adhesion, and cell polarity. Regulation of PCP signaling also occurs at the level of Dvl and its interactions with Vangl2 in the cilium and inturned (Int) and fuzzy (Fy) at the basal body.

Figure 3. Renal phenotypes of ciliopathies.

(A) Intravenous pyelogram of BBS kidney showing pyelocalyceal dilatation, calyceal clubbing, and pericalyceal cysts. (B) ADPKD kidneys typically have numerous cysts of variable sizes, with even distribution throughout the renal cortex and medulla. (C) ARPKD kidneys retain a reniform configuration with radiating, fusiform nonobstructive dilatations of the collecting ducts extending from the medulla to the cortex. (D) In NPH — as in JBTS, Senior-Loken Syndrome, and Jeune syndrome — the kidney exhibits cysts arising from the corticomedullary junction. (E) MKS kidneys manifest cystic dysplastic changes. Images reproduced with permission from Radiology (125) (A), Journal of the American Society of Nephrology (113) (D), and Advances in Anatomic Pathology (126) (B, C, and E). Scale bar: 1 cm.