2. Academic Validation
  3. HEATR2 plays a conserved role in assembly of the ciliary motile apparatus

HEATR2 plays a conserved role in assembly of the ciliary motile apparatus

  • PLoS Genet. 2014 Sep 18;10(9):e1004577. doi: 10.1371/journal.pgen.1004577.
Christine P Diggle 1,  Daniel J Moore 2,  Girish Mali 3,  Petra zur Lage 2,  Aouatef Ait-Lounis 4,  Miriam Schmidts 5,  Amelia Shoemark 6,  Amaya Garcia Munoz 7,  Mihail R Halachev 3,  Philippe Gautier 3,  Patricia L Yeyati 3,  David T Bonthron 1,  Ian M Carr 1,  Bruce Hayward 1,  Alexander F Markham 1,  Jilly E Hope 2,  Alex von Kriegsheim 7,  Hannah M Mitchison 5,  Ian J Jackson 3,  Bénédicte Durand 8,  Walter Reith 4,  Eamonn Sheridan 1,  Andrew P Jarman 2,  Pleasantine Mill 3
Affiliations

Affiliations

  • 1 School of Medicine, University of Leeds, Leeds, United Kingdom.
  • 2 Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
  • 3 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine at The University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
  • 4 Department of Pathology and Immunology, Faculty of Medicine, Université de Genève, Geneva, Switzerland.
  • 5 Molecular Medicine Unit and Birth Defect Research Center, Institute of Child Health, University College London, London, United Kingdom.
  • 6 Paediatric Respiratory Department, Royal Brompton Hospital, London, United Kingdom.
  • 7 Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.
  • 8 Centre de Génétique et de Physiologie Moléculaire et Cellulaire, UMR 5534 CNRS, Université Claude Bernard Lyon 1, Villeurbanne, France.
PMID: 25232951 DOI: 10.1371/journal.pgen.1004577
Abstract

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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