Journal
PLOS GENETICS
Volume 10, Issue 9, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1004577
Keywords
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Categories
Funding
- BBSRC
- EGRS
- CMVM
- Action Medical Research UK Clinical Training Fellowship [RTF-1411]
- Dutch Kidney Foundation [CP11.18]
- Milena Carvajal Pro-Kartagener Foundation
- Action Medical Research [GN2101]
- Newlife Foundation for Disabled Children UK [10-11/15]
- Fondation pour la Recherche Medicale [DEQ2000329168]
- ANR
- Swiss National Science Foundation
- Science Foundation Ireland [06/CE/B1129]
- Medical Research Council of Great Britain [MR/K018558/10]
- Medical Research Council of Great Britain
- Action Medical Research [2101] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BBS/E/D/20221657] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1299] Funding Source: researchfish
- Medical Research Council [MC_PC_U127561112, MC_U127561112, MC_UU_12018/26, MR/K018558/1, MR/L01629X/1] Funding Source: researchfish
- BBSRC [BBS/E/D/20221657] Funding Source: UKRI
- MRC [MC_UU_12018/26, MR/K018558/1, MC_PC_U127561112, MC_U127561112, MR/L01629X/1] Funding Source: UKRI
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Cilia are highly conserved microtubule-based structures that perform a variety of sensory and motility functions during development and adult homeostasis. In humans, defects specifically affecting motile cilia lead to chronic airway infections, infertility and laterality defects in the genetically heterogeneous disorder Primary Ciliary Dyskinesia (PCD). Using the comparatively simple Drosophila system, in which mechanosensory neurons possess modified motile cilia, we employed a recently elucidated cilia transcriptional RFX-FOX code to identify novel PCD candidate genes. Here, we report characterization of CG31320/HEATR2, which plays a conserved critical role in forming the axonemal dynein arms required for ciliary motility in both flies and humans. Inner and outer arm dyneins are absent from axonemes of CG31320 mutant flies and from PCD individuals with a novel splice-acceptor HEATR2 mutation. Functional conservation of closely arranged RFX-FOX binding sites upstream of HEATR2 orthologues may drive higher cytoplasmic expression of HEATR2 during early motile ciliogenesis. Immunoprecipitation reveals HEATR2 interacts with DNAI2, but not HSP70 or HSP90, distinguishing it from the client/chaperone functions described for other cytoplasmic proteins required for dynein arm assembly such as DNAAF1-4. These data implicate CG31320/HEATR2 in a growing intracellular pre-assembly and transport network that is necessary to deliver functional dynein machinery to the ciliary compartment for integration into the motile axoneme.
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