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Cell Cycle-Related Kinase (CCRK) regulates ciliogenesis and Hedgehog signaling in mice

The Hedgehog (Hh) signaling pathway plays a key role in cell fate specification, proliferation, and survival during mammalian development. Cells require a small organelle, the primary cilium, to respond properly to Hh signals and the key regulators of Hh signal transduction exhibit dynamic localizat...

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Autores principales: Snouffer, Ashley, Brown, Desmond, Lee, Hankyu, Walsh, Jonathon, Lupu, Floria, Norman, Ryan, Lechtreck, Karl, Ko, Hyuk Wan, Eggenschwiler, Jonathan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574612/
https://www.ncbi.nlm.nih.gov/pubmed/28817564
http://dx.doi.org/10.1371/journal.pgen.1006912
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author Snouffer, Ashley
Brown, Desmond
Lee, Hankyu
Walsh, Jonathon
Lupu, Floria
Norman, Ryan
Lechtreck, Karl
Ko, Hyuk Wan
Eggenschwiler, Jonathan
author_facet Snouffer, Ashley
Brown, Desmond
Lee, Hankyu
Walsh, Jonathon
Lupu, Floria
Norman, Ryan
Lechtreck, Karl
Ko, Hyuk Wan
Eggenschwiler, Jonathan
author_sort Snouffer, Ashley
collection PubMed
description The Hedgehog (Hh) signaling pathway plays a key role in cell fate specification, proliferation, and survival during mammalian development. Cells require a small organelle, the primary cilium, to respond properly to Hh signals and the key regulators of Hh signal transduction exhibit dynamic localization to this organelle when the pathway is activated. Here, we investigate the role of Cell Cycle Related kinase (CCRK) in regulation of cilium-dependent Hh signaling in the mouse. Mice mutant for Ccrk exhibit a variety of developmental defects indicative of inappropriate regulation of this pathway. Cell biological, biochemical and genetic analyses indicate that CCRK is required to control the Hedgehog pathway at the level or downstream of Smoothened and upstream of the Gli transcription factors, Gli2 and Gli3. In vitro experiments indicate that Ccrk mutant cells show a greater deficit in response to signaling over long time periods than over short ones. Similar to Chlamydomonas mutants lacking the CCRK homolog, LF2, mouse Ccrk mutant cells show defective regulation of ciliary length and morphology. Ccrk mutant cells exhibit defects in intraflagellar transport (the transport mechanism used to assemble cilia), as well as slowed kinetics of ciliary enrichment of key Hh pathway regulators. Collectively, the data suggest that CCRK positively regulates the kinetics by which ciliary proteins such as Smoothened and Gli2 are imported into the cilium, and that the efficiency of ciliary recruitment allows for potent responses to Hedgehog signaling over long time periods.
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spelling pubmed-55746122017-09-15 Cell Cycle-Related Kinase (CCRK) regulates ciliogenesis and Hedgehog signaling in mice Snouffer, Ashley Brown, Desmond Lee, Hankyu Walsh, Jonathon Lupu, Floria Norman, Ryan Lechtreck, Karl Ko, Hyuk Wan Eggenschwiler, Jonathan PLoS Genet Research Article The Hedgehog (Hh) signaling pathway plays a key role in cell fate specification, proliferation, and survival during mammalian development. Cells require a small organelle, the primary cilium, to respond properly to Hh signals and the key regulators of Hh signal transduction exhibit dynamic localization to this organelle when the pathway is activated. Here, we investigate the role of Cell Cycle Related kinase (CCRK) in regulation of cilium-dependent Hh signaling in the mouse. Mice mutant for Ccrk exhibit a variety of developmental defects indicative of inappropriate regulation of this pathway. Cell biological, biochemical and genetic analyses indicate that CCRK is required to control the Hedgehog pathway at the level or downstream of Smoothened and upstream of the Gli transcription factors, Gli2 and Gli3. In vitro experiments indicate that Ccrk mutant cells show a greater deficit in response to signaling over long time periods than over short ones. Similar to Chlamydomonas mutants lacking the CCRK homolog, LF2, mouse Ccrk mutant cells show defective regulation of ciliary length and morphology. Ccrk mutant cells exhibit defects in intraflagellar transport (the transport mechanism used to assemble cilia), as well as slowed kinetics of ciliary enrichment of key Hh pathway regulators. Collectively, the data suggest that CCRK positively regulates the kinetics by which ciliary proteins such as Smoothened and Gli2 are imported into the cilium, and that the efficiency of ciliary recruitment allows for potent responses to Hedgehog signaling over long time periods. Public Library of Science 2017-08-17 /pmc/articles/PMC5574612/ /pubmed/28817564 http://dx.doi.org/10.1371/journal.pgen.1006912 Text en © 2017 Snouffer et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Snouffer, Ashley
Brown, Desmond
Lee, Hankyu
Walsh, Jonathon
Lupu, Floria
Norman, Ryan
Lechtreck, Karl
Ko, Hyuk Wan
Eggenschwiler, Jonathan
Cell Cycle-Related Kinase (CCRK) regulates ciliogenesis and Hedgehog signaling in mice
title Cell Cycle-Related Kinase (CCRK) regulates ciliogenesis and Hedgehog signaling in mice
title_full Cell Cycle-Related Kinase (CCRK) regulates ciliogenesis and Hedgehog signaling in mice
title_fullStr Cell Cycle-Related Kinase (CCRK) regulates ciliogenesis and Hedgehog signaling in mice
title_full_unstemmed Cell Cycle-Related Kinase (CCRK) regulates ciliogenesis and Hedgehog signaling in mice
title_short Cell Cycle-Related Kinase (CCRK) regulates ciliogenesis and Hedgehog signaling in mice
title_sort cell cycle-related kinase (ccrk) regulates ciliogenesis and hedgehog signaling in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574612/
https://www.ncbi.nlm.nih.gov/pubmed/28817564
http://dx.doi.org/10.1371/journal.pgen.1006912
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