The Neuromodulator Adenosine Regulates Oligodendrocyte Migration at Motor Exit Point Transition Zones
Abstract
During development, oligodendrocyte progenitor cells (OPCs) migrate extensively throughout the spinal cord. However, their migration is restricted at transition zones (TZs). At these specialized locations, unique glial cells in both zebrafish and mice play a role in preventing peripheral OPC migration, but the mechanisms of this regulation are not understood. To elucidate the mechanisms that mediate OPC segregation at motor exit point (MEP) TZs, we performed an unbiased small-molecule screen. Using chemical screening and in vivo imaging, we discovered that inhibition of A2a adenosine receptors (ARs) causes ectopic OPC migration out of the spinal cord. We provide in vivo evidence that neuromodulation, partially mediated by adenosine, influences OPC migration specifically at the MEP TZ. This work opens exciting possibilities for understanding how OPCs reach their final destinations during development and identifies mechanisms that could promote their migration in disease.
Additional Information
© 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Received 5 January 2018, Revised 27 January 2019, Accepted 2 March 2019, Available online 2 April 2019. We would like to thank Drs. John Lazo and Elizabeth Sharlow for the LOPAC^(1280) library and for advice on designing the chemical screen. We thank Dr. Marcel Tawk for providing the pGEMTEZ-TeTxLC plasmid and Dr. Cody Smith for the UAS:GCaMP5 plasmid. We are extremely grateful to Lori Tocke for care and maintenance of the zebrafish facility and to all the members of the Kucenas lab and Dr. Dave Parichy for helpful comments and advice. This work was funded by the NIH through grants NS072212 and NS092070 (S.K.), NS070911 (D.A.P.), and NS101665 (D.A.P.) and by The Hartwell Foundation (S.K.). Author Contributions: L.F., T.G.W., and S.K. conceived the study, and L.F., T.G.W., M.P., and P.C. conducted and analyzed all of the experiments. A.V.G. and D.A.P. created the adora2aa TALEN mutant line. L.F., T.G.W., and S.K. wrote the manuscript with input from D.A.P. The authors declare no competing interests.Attached Files
Published - 1-s2.0-S2211124719303201-main.pdf
Accepted Version - nihms-1526190.pdf
Supplemental Material - 1-s2.0-S2211124719303201-mmc1.pdf
Files
1-s2.0-S2211124719303201-main.pdf
Additional details
Identifiers
- PMCID
- PMC6461400
- Eprint ID
- 94371
- Resolver ID
- CaltechAUTHORS:20190402-133417265
Funding
- NIH
- NS072212
- NIH
- NS092070
- NIH
- NS070911
- NIH
- NS101665
- Hartwell Foundation
Dates
- Created
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2019-04-02Created from EPrint's datestamp field
- Updated
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2022-03-01Created from EPrint's last_modified field