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PMID: 19996169 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 106 ·No. 51 ·2009-12-22 ·Pages 21666-71

Kim J, Kato M, Beachy PA

Abstract

Stimulation by the extracellular Hedgehog (Hh) protein signal has been shown to alter ciliary localization of the mammalian Hh receptor components Smoothened (Smo) and Patched (Ptc), and mutations that disrupt the structure and function of the cilium also disrupt Hh-induced changes in gene expression. But how ciliary events affect gene expression in the nucleus is not known, and to address this question we have characterized the cellular trafficking of Gli2, the principal mediator of Hh-dependent transcriptional activation. From a combination of pharmacological and genetic manipulations we find in resting cells that both Gli2 and Smo appear to shuttle in and out of the cilium, with Gli2 but not Smo requiring intact cytoplasmic microtubules for ciliary entry and both requiring the ciliary retrograde motor, cytoplasmic dynein 2, for ciliary exit. We also find that changes in ciliary and nuclear trafficking of Gli2 are triggered by the Hh-dependent accumulation of activated Smo in the cilium, resulting in a shift from primarily cytoplasmic localization to accumulation at the distal tip of the cilium and within the nucleus. Gli2 thus functions as a dynamic monitor of Smo activity in the cilium and thereby links Hh pathway activation in the cilium to transcriptional activation in the nucleus.

MeSH Terms
Animals Cell Nucleus/metabolism Cilia/metabolism Hedgehog Proteins/physiology Kruppel-Like Transcription Factors/metabolism Mice NIH 3T3 Cells Protein Transport Receptors, G-Protein-Coupled/metabolism Smoothened Receptor Transcriptional Activation Zinc Finger Protein Gli2
Chemicals
Gli2 protein, mouse Hedgehog Proteins Kruppel-Like Transcription Factors Receptors, G-Protein-Coupled Smo protein, mouse Smoothened Receptor Zinc Finger Protein Gli2
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Kim Jynho
Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Kato Masaki
Beachy Philip A
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0912180106
Published
2009-12-22
Epub
2009-00-08
Pages
21666-71
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2790365
Subset
IM
Grants
Howard Hughes Medical Institute · United States
External Links
PubMed source DOI: 10.1073/pnas.0912180106 PMC Full Text View journal details
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