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Atmin is a transcriptional regulator of both lung morphogenesis and ciliogenesis

Stevens, Jonathan L.; L. Stevens, J.; Goggolidou, Paraskevi; 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.

Authors

Jonathan L. Stevens

J. L. Stevens

Paraskevi Goggolidou

Francesco Agueci

Jennifer Keynton

Daniel T. Grimes

Saloni H. Patel

Helen Hilton

Stine K. Morthorst

Antonella Dipaolo

Debbie J. Williams

Jeremy Sanderson

Svetlana V. Khoronenkova

Nicola Powles-Glover

Alexander Ermakov

Chris T. Esapa

Rosario Romero

Grigory L. Dianov

James Briscoe

Colin A. Johnson

Lotte B. Pedersen

Dominic P. Norris



Abstract

© 2014. Initially identified in DNA damage repair, ATM-interactor (ATMIN) further functions as a transcriptional regulator of lung morphogenesis. Here we analyse three mouse mutants, Atmingpg6/gpg6, AtminH210Q/H210Q and Dynll1GT/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, Dynll1GT/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.

Journal Article Type Article
Publication Date Oct 1, 2014
Journal Development (Cambridge)
Print ISSN 1011-6370
Electronic ISSN 1477-9129
Publisher Palgrave Macmillan
Peer Reviewed Peer Reviewed
Volume 141
Issue 20
Pages 3966-3977
APA6 Citation Stevens, J. L., Goggolidou, P., L. Stevens, J., Agueci, F., Keynton, J., Wheway, G., …Norris, D. P. (2014). Atmin is a transcriptional regulator of both lung morphogenesis and ciliogenesis. Development, 141(20), 3966-3977. https://doi.org/10.1242/dev.107755
DOI https://doi.org/10.1242/dev.107755
Keywords asciz, atmin, ciliogenesis, ciliopathy, Dynll1, mouse
Publisher URL http://dx.doi.org/10.1242/dev.107755

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