Abstract
Mutations in genes affecting primary cilia cause ciliopathies, a diverse group of disorders often affecting skeletal development. This includes Jeune syndrome or asphyxiating thoracic dystrophy (ATD), an autosomal recessive skeletal disorder. Unraveling the responsible molecular pathology helps illuminate mechanisms responsible for functional primary cilia. We identified two families with ATD caused by loss‐of‐function mutations in the gene encoding adrenergic receptor kinase 1 (ADRBK1 or GRK2). GRK2 cells from an affected individual homozygous for the p.R158* mutation resulted in loss of GRK2, and disrupted chondrocyte growth and differentiation in the cartilage growth plate. GRK2 null cells displayed normal cilia morphology, yet loss of GRK2 compromised cilia‐based signaling of Hedgehog (Hh) pathway. Canonical Wnt signaling was also impaired, manifested as a failure to respond to Wnt ligand due to impaired phosphorylation of the Wnt co‐receptor LRP6. We have identified GRK2 as an essential regulator of skeletogenesis and demonstrate how both Hh and Wnt signaling mechanistically contribute to skeletal ciliopathies.
Highlights
A single primary cilium protrudes from nearly every post-mitotic vertebrate cell, and cilia sense and transduce a vast array of extracellular cues
These data contrast with findings in mouse cells, in which the SMO accumulation was abrogated only at one case, i.e., in Grk2À/À NIH3T3 cells that were primed toward chondrocytes in micromass culture
In undifferentiated Grk2À/À NIH3T3 cells, in NIH3T3 cells treated with Grk2 inhibitors (Zhao et al, 2016; Pusapati et al, 2018) or in IMCD3 cells with downregulated Grk2, the SMO accumulated in cilia upon Smoothened agonist (SAG) normally, despite its underphosphorylation (Fig EV3)
Summary
A single primary cilium protrudes from nearly every post-mitotic vertebrate cell, and cilia sense and transduce a vast array of extracellular cues. Cilia utilize intraflagellar transport (IFT), a bidirectional system that builds and maintains the cilium while facilitating protein entry, exit and trafficking through the organelle. IFT is governed by a large multimeric protein complex with two main subcomplexes, IFT-A and IFT-B. The anterograde IFT is driven by the kinesin motor KIF3 and mediates transport from the base to the tip of cilia, while retrograde IFT is driven by the dynein-2 motor and transports cargo from the tip to the base of the cilium (Kozminski et al, 1993). Vertebrate primary cilia act as signaling centers for the Hedgehog (Hh) family of morphogens a 2020 The Authors.
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