2025/12/01 by Miriam Schmidts · 1 voice
Medicine · Biochemistry, Genetics and Molecular Biology · #Cystic Fibrosis Research Advances #Genetic and Kidney Cyst Diseases #Microtubule and mitosis dynamics
paper · doi:10.1242/dmm.052754
openalex publication_date 2025/12/01 · openalex created_date 2025/12/19 · openalex updated_date 2026/06/20
Cilia motility disturbances or lack of motile cilia can result in disturbances of the left–right body axis (laterality defects), as well as reduced fertility and impaired airway clearance causing recurrent airway infections, subsequently leading to destruction of the airways and lung tissue. In humans, this detrimental condition is termed mucociliary clearance disorder or, in the case of disturbed cilia motility, primary ciliary dyskinesia (PCD). Over the past two decades, dysfunction of a large number of genes – most encoding components of the ciliary motility apparatus itself, such as dynein arm components, dynein arm assembly factors or dynein arm docking complex components – has been identified as the underlying cause of PCD in humans. This includes dysfunction of LRRC56, a protein previously thought to be involved in outer dynein arm (ODA) transport, but its precise function had remained unclear.In this paper, Reyes-Nava, Wallingford, Marcotte and colleagues use Xenopus multiciliated cells (MCCs) to shed light on LRRC56 function in vertebrates. First, they show that LRRC56 localisation is consistent with a role for Lrrc56 in dynein arm assembly in the cytoplasm before import into the cilium and that Lrrc56 is also required for ODA localisation to the distal axoneme of the cilium in Xenopus. This suggests spatial regulation of docking complex activity along the proximodistal axis in Xenopus MCCs, although ciliary ultrastructure was previously reported as normal for patients with PCD with biallelic LRRC56 variants using electron microscopy. Possibly, distal ODA defects were missed in these patients or, less likely, this could be the result of a Xenopus-specific effect. Using in vivo affinity purification-mass spectrometry, the authors also identify outer dynein arm docking complex protein (Odad)1 and Odad3 as Lrrc56 protein complex partners. This experiment cannot determine whether this interaction is direct or indirect, but the findings overall confirm previous observations in trypanosomes that LRRC56 is required for distal ODA docking. Last, but not least, the authors demonstrate that human LRRC56 disease alleles result in different basal body and axonemal localisation defects depending on which protein domains are affected by the specific variant.This study provides a beautiful example of how Xenopus MCC models can be used to study vertebrate motile cilia, including dissecting the effects of human disease alleles and shedding light on ODA ciliary targeting in vertebrates. PCD can be difficult to diagnose, especially when only subtle motility defects are detectable in cilia videomicroscopy. Visualisation of the absence of ODAs in the distal part of patient nasal cilia would provide a helpful diagnostic tool.