title: ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis.
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.
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Goggolidou
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Stevens
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Agueci
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keynton
authors.affiliation: 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.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Wheway
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Grimes
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Saloni H
authors.initials: SH
authors.lastname: Patel
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Hilton
authors.affiliation: Department of Biology, University of Copenhagen, Universitetsparken 13, Copenhagen, OE DK-2100, Denmark.
authors.forename: Stine K
authors.initials: SK
authors.lastname: Morthorst
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Antonella
authors.initials: A
authors.lastname: DiPaolo
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Debbie J
authors.initials: DJ
authors.lastname: Williams
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sanderson
authors.affiliation: 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.
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Khoronenkova
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Powles-Glover
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ermakov
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Chris T
authors.initials: CT
authors.lastname: Esapa
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Rosario
authors.initials: R
authors.lastname: Romero
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Grigory L
authors.initials: GL
authors.lastname: Dianov
authors.affiliation: MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: James
authors.initials: J
authors.lastname: Briscoe
authors.affiliation: 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.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.affiliation: Department of Biology, University of Copenhagen, Universitetsparken 13, Copenhagen, OE DK-2100, Denmark.
authors.forename: Lotte B
authors.initials: LB
authors.lastname: Pedersen
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK d.norris@har.mrc.ac.uk.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Norris
mesh_terms: D000818:Animals; D002696:Chlamydomonas / Q000378:metabolism; D002923:Cilia / Q000378:metabolism / Q000502:physiology*; D056445:Cytoplasmic Dyneins; D004249:DNA Damage; D004398:Dyneins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005819:Genetic Markers; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000196:embryology*; D051379:Mice; D009154:Mutation; D010641:Phenotype; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: C554480:ATMIN protein, mouse; D005819:Genetic Markers; D053823:Hedgehog Proteins; D014157:Transcription Factors; D056445:Cytoplasmic Dyneins; C576160:DYNLL1 protein, mouse; D004398:Dyneins
keywords: Asciz; Atmin; Ciliogenesis; Ciliopathy; Dynll1; Mouse