ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis

Paraskevi Goggolidou; Jonathan L. Stevens; Francesco  Agueci; Jennifer Keynton; Gabrielle Wheway; Daniel T. Grimes; Saloni H. Patel; Helen Hilton; Stine Kjær 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 Bang Pedersen; Dominic P. Norris

doi:10.1242/dev.107755

ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis

Paraskevi Goggolidou, Jonathan L. Stevens, Francesco Agueci, Jennifer Keynton, Gabrielle Wheway, Daniel T. Grimes, Saloni H. Patel, Helen Hilton, Stine Kjær 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. JohnsonLotte Bang Pedersen, Dominic P. Norris

Cell Biology and Physiology

31 Citations (Scopus)

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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.

Original language	English
Journal	Development
Volume	141
Pages (from-to)	3966-3977
Number of pages	12
ISSN	0950-1991
DOIs	https://doi.org/10.1242/dev.107755
Publication status	Published - 1 Oct 2014

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ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesisFinal published version, 1.33 MB

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Goggolidou, P., L. Stevens, J., Agueci, F., Keynton, J., Wheway, G., T. Grimes, D., H. Patel, S., Hilton, H., Morthorst, S. K., DiPaolo, A., J. Williams, D., Sanderson, J., V. Khoronenkova, S., Powles-Glover, N., Ermakov, A., T. Esapa, C., Romero, R., L. Dianov, G., Briscoe, J., ... P. Norris, D. (2014). ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis. Development, 141, 3966-3977. https://doi.org/10.1242/dev.107755

Goggolidou, P, L. Stevens, J, Agueci, F, Keynton, J, Wheway, G, T. Grimes, D, H. Patel, S, Hilton, H, Morthorst, SK, DiPaolo, A, J. Williams, D, Sanderson, J, V. Khoronenkova, S, Powles-Glover, N, Ermakov, A, T. Esapa, C, Romero, R, L. Dianov, G, Briscoe, J, A. Johnson, C, Pedersen, LB & P. Norris, D 2014, 'ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis', Development, vol. 141, pp. 3966-3977. https://doi.org/10.1242/dev.107755

@article{26657abadb8c461195d8c3e162165631,

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, 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.",

author = "Paraskevi Goggolidou and {L. Stevens}, Jonathan and Francesco Agueci and Jennifer Keynton and Gabrielle Wheway and {T. Grimes}, Daniel and {H. Patel}, Saloni and Helen Hilton and Morthorst, {Stine Kj{\ae}r} and Antonella DiPaolo and {J. Williams}, Debbie and Jeremy Sanderson and {V. Khoronenkova}, Svetlana and Nicola Powles-Glover and Alexander Ermakov and {T. Esapa}, Chris and Rosario Romero and {L. Dianov}, Grigory and James Briscoe and {A. Johnson}, Colin and Pedersen, {Lotte Bang} and {P. Norris}, Dominic",

year = "2014",

month = oct,

day = "1",

doi = "10.1242/dev.107755",

language = "English",

volume = "141",

pages = "3966--3977",

journal = "Development",

issn = "0950-1991",

publisher = "The Company of Biologists",

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TY - JOUR

T1 - ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis

AU - Goggolidou, Paraskevi

AU - L. Stevens, Jonathan

AU - Agueci, Francesco

AU - Keynton, Jennifer

AU - Wheway, Gabrielle

AU - T. Grimes, Daniel

AU - H. Patel, Saloni

AU - Hilton, Helen

AU - Morthorst, Stine Kjær

AU - DiPaolo, Antonella

AU - J. Williams, Debbie

AU - Sanderson, Jeremy

AU - V. Khoronenkova, Svetlana

AU - Powles-Glover, Nicola

AU - Ermakov, Alexander

AU - T. Esapa, Chris

AU - Romero, Rosario

AU - L. Dianov, Grigory

AU - Briscoe, James

AU - A. Johnson, Colin

AU - Pedersen, Lotte Bang

AU - P. Norris, Dominic

PY - 2014/10/1

Y1 - 2014/10/1

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, 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.

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, 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.

U2 - 10.1242/dev.107755

DO - 10.1242/dev.107755

M3 - Journal article

C2 - 25294941

SN - 0950-1991

VL - 141

SP - 3966

EP - 3977

JO - Development

JF - Development

ER -

ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis

Abstract

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