2. Academic Validation
  3. ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis

ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis

  • Development. 2014 Oct;141(20):3966-77. doi: 10.1242/dev.107755.
Paraskevi Goggolidou 1,  Jonathan L Stevens 1,  Francesco Agueci 1,  Jennifer Keynton 1,  Gabrielle Wheway 2,  Daniel T Grimes 1,  Saloni H Patel 1,  Helen Hilton 1,  Stine K Morthorst 3,  Antonella DiPaolo 1,  Debbie J Williams 1,  Jeremy Sanderson 1,  Svetlana V Khoronenkova 4,  Nicola Powles-Glover 1,  Alexander Ermakov 1,  Chris T Esapa 1,  Rosario Romero 1,  Grigory L Dianov 5,  James Briscoe 6,  Colin A Johnson 2,  Lotte B Pedersen 3,  Dominic P Norris 7
Affiliations

Affiliations

  • 1 Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
  • 2 Section of Ophthalmology and Neurosciences, Wellcome Trust Brenner Building, Leeds Institute of Molecular Medicine, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
  • 3 Department of Biology, University of Copenhagen, Universitetsparken 13, Copenhagen, OE DK-2100, Denmark.
  • 4 Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1-11, Moscow 119991, Russia.
  • 5 Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
  • 6 MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
  • 7 Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK d.norris@har.mrc.ac.uk.
PMID: 25294941 DOI: 10.1242/dev.107755
Abstract

Initially identified in DNA damage repair, ATM-interactor (ATMIN) further functions as a transcriptional regulator of lung morphogenesis. Here we analyse three mouse mutants, Atmin(gpg6/gpg6), Atmin(H210Q/H210Q) and Dynll1(GT/GT), revealing how ATMIN and its transcriptional target dynein light chain LC8-type 1 (DYNLL1) are required for normal lung morphogenesis and ciliogenesis. Expression screening of ciliogenic genes confirmed Dynll1 to be controlled by ATMIN and further revealed moderately altered expression of known intraflagellar transport (IFT) protein-encoding loci in Atmin mutant embryos. Significantly, Dynll1(GT/GT) embryonic cilia exhibited shortening and bulging, highly similar to the characterised retrograde IFT phenotype of Dync2h1. Depletion of ATMIN or DYNLL1 in cultured cells recapitulated the in vivo ciliogenesis phenotypes and expression of DYNLL1 or the related DYNLL2 rescued the effects of loss of ATMIN, demonstrating that ATMIN primarily promotes ciliogenesis by regulating Dynll1 expression. Furthermore, DYNLL1 as well as DYNLL2 localised to cilia in puncta, consistent with IFT particles, and physically interacted with WDR34, a mammalian homologue of the Chlamydomonas cytoplasmic dynein 2 intermediate chain that also localised to the cilium. This study extends the established Atmin-Dynll1 relationship into a developmental and a ciliary context, uncovering a novel series of interactions between DYNLL1, WDR34 and ATMIN. This identifies potential novel components of cytoplasmic dynein 2 and furthermore provides fresh insights into the molecular pathogenesis of human skeletal ciliopathies.

Keywords

Asciz; Atmin; Ciliogenesis; Ciliopathy; Dynll1; Mouse.

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