TY - JOUR
T1 - ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis
AU - Powles-Glover, Nicola
AU - Ermakov, Alexander
AU - Esapa, Chris T.
AU - Romero, Rosario
AU - Dianov, Grigory L.
AU - Briscoe, James
AU - Johnson, Colin A.
AU - Pedersen, Lotte
AU - Norris, Dominic P.
AU - Stevens, Jonathan L.
AU - Agueci, Francesco
AU - Keynton, Jennifer
AU - Wheway, Gabrielle
AU - Grimes, Daniel T.
AU - Patel, Saloni H.
AU - Hilton, Helen
AU - Morthorst, Stine K.
AU - DiPaolo, Antonella
AU - Williams, Debbie J.
AU - Sanderson, Jeremy
AU - Khoronenkova, Svetlana V.
AU - Goggolidou, Paraskevi
N1 - Note: This work was supported by the Medical Research Council [grant number MC_U142670370], the European Community's Seventh Framework Programme [grant number FP7/2009 [241955 SYSCILIA]] and the University of Copenhagen.
PY - 2014/10/31
Y1 - 2014/10/31
N2 - 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
AB - 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
KW - Biological sciences
UR - http://www.ncbi.nlm.nih.gov/pubmed/25294941
U2 - 10.1242/dev.107755
DO - 10.1242/dev.107755
M3 - Article
C2 - 25294941
SN - 0950-1991
VL - 141
SP - 3966
EP - 3977
JO - Development
JF - Development
ER -