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ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis

Goggolidou, Paraskevi
; 
Stevens, Jonathan L
; 
Agueci, Francesco
; 
Keynton, Jennifer
; 
Wheway, Gabrielle
; 
Grimes, Daniel T
; 
Patel, Saloni H
; 
Hilton, Helen
; 
Morthorst, Stine K
; 
DiPaolo, Antonella
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Authors
Goggolidou, Paraskevi
 Stevens, Jonathan L
 Agueci, Francesco
 Keynton, Jennifer
 Wheway, Gabrielle
 Grimes, Daniel T
 Patel, Saloni H
 Hilton, Helen
 Morthorst, Stine K
 DiPaolo, Antonella
 Williams, Debbie J
 Sanderson, Jeremy
 Khoronenkova, Svetlana V
 Powles-Glover, Nicola
 Ermakov, Alexander
 Esapa, Chris T
 Romero, Rosario
 Dianov, Grigory L
 Briscoe, James
 Johnson, Colin A
 Pedersen, Lotte B
 Norris, Dominic P
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Issue Date
2014-10-07
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Subjects
Asciz
 Atmin
 Ciliogenesis
 Ciliopathy
 Dynll1
 Mouse
 Cilia
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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.
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Publisher
Company of Biologists
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Development
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http://hdl.handle.net/2436/621803
DOI
10.1242/dev.107755
PubMed ID
25294941
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http://dev.biologists.org/content/141/20/3966
Type
Journal article
Language
en
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© 2014 The Authors. Published by The Company of Biologists. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1242/dev.107755
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Faculty of Science and Engineering