Broad-Minded Links Cell Cycle-Related Kinase to Cilia Assembly and Hedgehog Signal Transduction

Hyuk Wan Ko; Ryan X. Norman; John Tran; Kimberly P. Fuller; Mitsunori Fukuda; Jonathan T. Eggenschwiler

doi:10.1016/j.devcel.2009.12.014

Broad-Minded Links Cell Cycle-Related Kinase to Cilia Assembly and Hedgehog Signal Transduction

Hyuk Wan Ko, Ryan X. Norman, John Tran, Kimberly P. Fuller, Mitsunori Fukuda, Jonathan T. Eggenschwiler

Department of Biochemistry

Research output: Contribution to journal › Article › peer-review

85 Citations (Scopus)

Abstract

Recent findings indicate that mammalian Sonic hedgehog (Shh) signal transduction occurs within primary cilia, although the cell biological mechanisms underlying both Shh signaling and ciliogenesis have not been fully elucidated. We show that an uncharacterized TBC domain-containing protein, Broad-minded (Bromi), is required for high-level Shh responses in the mouse neural tube. We find that Bromi controls ciliary morphology and proper Gli2 localization within the cilium. By use of a zebrafish model, we further show that Bromi is required for proper association between the ciliary membrane and axoneme. Bromi physically interacts with cell cycle-related kinase (CCRK), whose Chlamydomonas homolog regulates flagellar length. Biochemical and genetic interaction data indicate that Bromi promotes CCRK stability and function. We propose that Bromi and CCRK control the structure of the primary cilium by coordinating assembly of the axoneme and ciliary membrane, allowing Gli proteins to be properly activated in response to Shh signaling.

Original language	English
Pages (from-to)	237-247
Number of pages	11
Journal	Developmental Cell
Volume	18
Issue number	2
DOIs	https://doi.org/10.1016/j.devcel.2009.12.014
Publication status	Published - 2010 Feb 16

Bibliographical note

Funding Information:
We thank members of K. Anderson and L. Niswander's laboratories for help with the mutagenesis screen, K. Anderson, M. Scott, A. Joyner, T. Caspary, G. Pazour, R. Fisher, X. Sun, and BayGenomics for contributing mouse lines, cell lines, and reagents, J. Goodhouse, M. Bisher, J. Levorse, S. Kyin, Y. Lin, and J. Schottenfeld for technical assistance, and R. Burdine and T. Caspary for comments on the manuscript. Monoclonal antibodies against Shh, FoxA2/Hnf3β, Nkx2.2, Nkx6.1, HB9/Mnr2, Pax6, and Pax7 were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa, Department of Biological Sciences, Iowa City, Iowa. This work was supported by New Jersey Commission on Spinal Cord Research (NJCSCR) grant 07-3069-SCR-E-0 and U.S. National Institutes of Health grant R01 HD050761. H.W.K. was supported by a postdoctoral fellowship from the NJCSCR.

All Science Journal Classification (ASJC) codes

Molecular Biology
Biochemistry, Genetics and Molecular Biology(all)
Developmental Biology
Cell Biology

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10.1016/j.devcel.2009.12.014

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@article{884e9e927aa24840843ba1839b7ce515,

title = "Broad-Minded Links Cell Cycle-Related Kinase to Cilia Assembly and Hedgehog Signal Transduction",

abstract = "Recent findings indicate that mammalian Sonic hedgehog (Shh) signal transduction occurs within primary cilia, although the cell biological mechanisms underlying both Shh signaling and ciliogenesis have not been fully elucidated. We show that an uncharacterized TBC domain-containing protein, Broad-minded (Bromi), is required for high-level Shh responses in the mouse neural tube. We find that Bromi controls ciliary morphology and proper Gli2 localization within the cilium. By use of a zebrafish model, we further show that Bromi is required for proper association between the ciliary membrane and axoneme. Bromi physically interacts with cell cycle-related kinase (CCRK), whose Chlamydomonas homolog regulates flagellar length. Biochemical and genetic interaction data indicate that Bromi promotes CCRK stability and function. We propose that Bromi and CCRK control the structure of the primary cilium by coordinating assembly of the axoneme and ciliary membrane, allowing Gli proteins to be properly activated in response to Shh signaling.",

author = "Ko, {Hyuk Wan} and Norman, {Ryan X.} and John Tran and Fuller, {Kimberly P.} and Mitsunori Fukuda and Eggenschwiler, {Jonathan T.}",

note = "Funding Information: We thank members of K. Anderson and L. Niswander's laboratories for help with the mutagenesis screen, K. Anderson, M. Scott, A. Joyner, T. Caspary, G. Pazour, R. Fisher, X. Sun, and BayGenomics for contributing mouse lines, cell lines, and reagents, J. Goodhouse, M. Bisher, J. Levorse, S. Kyin, Y. Lin, and J. Schottenfeld for technical assistance, and R. Burdine and T. Caspary for comments on the manuscript. Monoclonal antibodies against Shh, FoxA2/Hnf3β, Nkx2.2, Nkx6.1, HB9/Mnr2, Pax6, and Pax7 were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa, Department of Biological Sciences, Iowa City, Iowa. This work was supported by New Jersey Commission on Spinal Cord Research (NJCSCR) grant 07-3069-SCR-E-0 and U.S. National Institutes of Health grant R01 HD050761. H.W.K. was supported by a postdoctoral fellowship from the NJCSCR. ",

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doi = "10.1016/j.devcel.2009.12.014",

language = "English",

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AU - Norman, Ryan X.

AU - Tran, John

AU - Fuller, Kimberly P.

AU - Fukuda, Mitsunori

AU - Eggenschwiler, Jonathan T.

N1 - Funding Information: We thank members of K. Anderson and L. Niswander's laboratories for help with the mutagenesis screen, K. Anderson, M. Scott, A. Joyner, T. Caspary, G. Pazour, R. Fisher, X. Sun, and BayGenomics for contributing mouse lines, cell lines, and reagents, J. Goodhouse, M. Bisher, J. Levorse, S. Kyin, Y. Lin, and J. Schottenfeld for technical assistance, and R. Burdine and T. Caspary for comments on the manuscript. Monoclonal antibodies against Shh, FoxA2/Hnf3β, Nkx2.2, Nkx6.1, HB9/Mnr2, Pax6, and Pax7 were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa, Department of Biological Sciences, Iowa City, Iowa. This work was supported by New Jersey Commission on Spinal Cord Research (NJCSCR) grant 07-3069-SCR-E-0 and U.S. National Institutes of Health grant R01 HD050761. H.W.K. was supported by a postdoctoral fellowship from the NJCSCR.

PY - 2010/2/16

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N2 - Recent findings indicate that mammalian Sonic hedgehog (Shh) signal transduction occurs within primary cilia, although the cell biological mechanisms underlying both Shh signaling and ciliogenesis have not been fully elucidated. We show that an uncharacterized TBC domain-containing protein, Broad-minded (Bromi), is required for high-level Shh responses in the mouse neural tube. We find that Bromi controls ciliary morphology and proper Gli2 localization within the cilium. By use of a zebrafish model, we further show that Bromi is required for proper association between the ciliary membrane and axoneme. Bromi physically interacts with cell cycle-related kinase (CCRK), whose Chlamydomonas homolog regulates flagellar length. Biochemical and genetic interaction data indicate that Bromi promotes CCRK stability and function. We propose that Bromi and CCRK control the structure of the primary cilium by coordinating assembly of the axoneme and ciliary membrane, allowing Gli proteins to be properly activated in response to Shh signaling.

AB - Recent findings indicate that mammalian Sonic hedgehog (Shh) signal transduction occurs within primary cilia, although the cell biological mechanisms underlying both Shh signaling and ciliogenesis have not been fully elucidated. We show that an uncharacterized TBC domain-containing protein, Broad-minded (Bromi), is required for high-level Shh responses in the mouse neural tube. We find that Bromi controls ciliary morphology and proper Gli2 localization within the cilium. By use of a zebrafish model, we further show that Bromi is required for proper association between the ciliary membrane and axoneme. Bromi physically interacts with cell cycle-related kinase (CCRK), whose Chlamydomonas homolog regulates flagellar length. Biochemical and genetic interaction data indicate that Bromi promotes CCRK stability and function. We propose that Bromi and CCRK control the structure of the primary cilium by coordinating assembly of the axoneme and ciliary membrane, allowing Gli proteins to be properly activated in response to Shh signaling.

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ER -

Broad-Minded Links Cell Cycle-Related Kinase to Cilia Assembly and Hedgehog Signal Transduction

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

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