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Calcium oscillations coordinate feather mesenchymal cell movement by SHH dependent modulation of gap junction networks

Li, Ang and Cho, Jung-Hwa and Reid, Brian and Tseng, Chun-Chih and He, Lian and Tan, Peng and Yeh, Chao-Yuan and Wu, Ping and Li, Yuwei and Widelitz, Randall B. and Zhou, Yubin and Zhao, Min and Chow, Robert H. and Chuong, Cheng-Ming (2018) Calcium oscillations coordinate feather mesenchymal cell movement by SHH dependent modulation of gap junction networks. Nature Communications, 9 . Art. No. 5377. ISSN 2041-1723. PMCID PMC6299091. http://resolver.caltech.edu/CaltechAUTHORS:20181221-080227359

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Abstract

Collective cell migration mediates multiple tissue morphogenesis processes. Yet how multi-dimensional mesenchymal cell movements are coordinated remains mostly unknown. Here we report that coordinated mesenchymal cell migration during chicken feather elongation is accompanied by dynamic changes of bioelectric currents. Transcriptome profiling and functional assays implicate contributions from functional voltage-gated Ca^(2+) channels (VGCCs), Connexin-43 based gap junctions, and Ca^(2+) release activated Ca^(2+) (CRAC) channels. 4-Dimensional Ca^(2+) imaging reveals that the Sonic hedgehog-responsive mesenchymal cells display synchronized Ca^(2+) oscillations, which expand progressively in area during feather elongation. Inhibiting VGCCs, gap junctions, or Sonic hedgehog signaling alters the mesenchymal Ca^(2+) landscape, cell movement patterns and feather bud elongation. Ca^(2+) oscillations induced by cyclic activation of opto-cCRAC channels enhance feather bud elongation. Functional disruption experiments and promoter analysis implicate synergistic Hedgehog and WNT/β-Catenin signaling in activating Connexin-43 expression, establishing gap junction networks synchronizing the Ca^(2+) profile among cells, thereby coordinating cell movement patterns.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41467-018-07661-5DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299091PubMed CentralArticle
ORCID:
AuthorORCID
Li, Yuwei0000-0001-7753-4869
Zhou, Yubin0000-0001-7962-0517
Zhao, Min0000-0002-2500-3035
Additional Information:© 2018 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 21 March 2017; Accepted 14 November 2018; Published 18 December 2018. Data availability: RNA-Seq data have been deposited in the NCBI GEO database under accession code GSE86251. The ChIP-Seq data have been deposited in the GEO database under accession code is GSE122049. The authors declare that all other data supporting the findings of this study are available within the article and its Supplementary Information files, or are available from the authors upon request. C-.M.C., A.L., R.B.W. and P.W. are supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) R01-AR47364, AR60306, GM125322. A.L. is also supported by California Institute of Regenerative Medicine (CIRM) training grant TG2-01161 and Doerr Stem Cell Challenge Grant. J-.H.C., R.H.C. are supported by NIH BRP 5R01EY022931. B.R., M.Z. are supported by grants from AFOSR (FA9550-16-1-0052), NIH (1R01EY019101), NEI Core Grant (P30 EY012576, to J.S. Werner) and Research to Prevent Blindness. L.H., T.P., Y.Z. are supported by NIH R01-GM112003, R21-GM126532 and the Welch Foundation. We thank Dr. James Briscoe (Francis Crick Institute, United Kingdom) for providing the GBS-GFP plasmid. We thank Drs. Tingxin Jiang, Ya-Chen Liang, Jie Yan, Mingxing Lei, Masafumi Inaba, and other Chuong Lab members for their support. We thank USC Stem Cell Microscopy Core Facility and the Cell and Tissue Imaging Core, USC Research Center for Liver Disease for assistance in imaging (NIH P30DK048522); USC Epigenome Center for sequencing; Yibu Chen and Meng Li of the USC Norris Medical Library Bioinformatics Service for assistance in RNA-Seq and ChIP-Seq analysis. Author Contributions: A.L., J-.H.C., C-.M.C., and R.H.C. conceived the overall experimental designs. M.Z., B.R., and C-.M.C designed the vibrating probe assay and B.R. conducted the experiments. J-.H.C. and A.L. conducted and analyzed time-lapse Ca^(2+) imaging data obtained from skin explants and strips. J-.H.C. and R.H.C. conducted single cell Ca^(2+) imaging, immunostaining, patch clamp experiment and analyzed the data. C-.Y.Y. wrote an intensity modulated display analysis routine to generate ratiometric Ca^(2+) images. A.L. conducted the 4D Ca^(2+) imaging, 4D cell nuclear imaging. Y.L., R.B.W., and A.L. analyzed the 4D data. C-.C.T and A.L. conducted the scrape-loading dye transfer assay. L.H., P.T., Y.Z., and A.L. designed the opto-cCRAC experiments and A.L. conducted the experiments. P.W. did the RNA-Seq, ChIP-Seq sample preparation and A.L. did analysis of the data. A.L. designed the shRNA for pLL3.7 and P.W. did the cloning. A.L. conducted the in situ hybridization, immunostaining experiments. A.L., J-.H.C., R.B.W., R.H.C., and C-.M.C. contributed to manuscript writing and editing. This is a multi-disciplinary study. C-.M.C. contributed more on feather bud morphogenesis and R.H.C. contributed more on ion channel and Ca^(2+)-signaling. The authors declare no competing interests.
Funders:
Funding AgencyGrant Number
NIHR01-AR47364
NIHR01-AR60306
NIHGM125322
California Institute for Regenerative Medicine (CIRM)TG2-01161
Doerr Stem Cell Challenge GrantUNSPECIFIED
NIH5R01EY022931
Air Force Office of Scientific Research (AFOSR)FA9550-16-1-0052
NIH1R01EY019101
National Eye InstituteP30 EY012576
Research to Prevent BlindnessUNSPECIFIED
NIHR01-GM112003
NIHR21-GM126532
Robert A. Welch FoundationC-1845
NIHP30DK048522
PubMed Central ID:PMC6299091
Record Number:CaltechAUTHORS:20181221-080227359
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20181221-080227359
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:91943
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Dec 2018 17:08
Last Modified:21 Dec 2018 17:08

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