Draxin acts as a molecular rheostat of canonical Wnt signaling to control cranial neural crest EMT

Creators: Hutchins, Erica J.; Bronner, Marianne E.

Abstract

Neural crest cells undergo a spatiotemporally regulated epithelial-to-mesenchymal transition (EMT) that proceeds head to tailward to exit from the neural tube. In this study, we show that the secreted molecule Draxin is expressed in a transient rostrocaudal wave that mirrors this emigration pattern, initiating after neural crest specification and being down-regulated just before delamination. Functional experiments reveal that Draxin regulates the timing of cranial neural crest EMT by transiently inhibiting canonical Wnt signaling. Ectopic maintenance of Draxin in the cranial neural tube blocks full EMT; while cells delaminate, they fail to become mesenchymal and migratory. Loss of Draxin results in premature delamination but also in failure to mesenchymalize. These results suggest that a pulse of intermediate Wnt signaling triggers EMT and is necessary for its completion. Taken together, these data show that transient secreted Draxin mediates proper levels of canonical Wnt signaling required to regulate the precise timing of initiation and completion of cranial neural crest EMT.

Additional Information

© 2018 Hutchins and Bronner. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). Submitted: 28 September 2017; Revision received 24 May 2018; Accepted: 5 July 2018. We thank Dr. M. Simões-Costa (Cornell University, Ithaca, NY) for providing the NC1.1M3:EGFP construct, Dr. X. He (Boston Children's Hospital, Harvard Medical School, Boston, MA) for providing the human LRP5 plasmid, and Dr. S. Chapman (Clemson University, Clemson, SC) for providing the chick Dkk-1 probe template. We also thank Dr. M. Piacentino and S. Wilbert for technical assistance, Shashank Gandhi and Dr. Ruth Williams for helpful CRISPR suggestions, Drs. M. Martik, R. Uribe, and M. Piacentino for critical manuscript comments, and M. Maline for illustrations. This work was supported by a National Institutes of Health grant (R01DE024157 to M.E. Bronner) and a Ruth L. Kirschstein National Research Service Award (F32DE026355 to E.J. Hutchins). The authors declare no competing financial interests. Author contributions: E.J. Hutchins and M.E. Bronner conceived and designed the experimental approach. E.J. Hutchins performed the experiments and analyzed the data. E.J. Hutchins and M.E. Bronner wrote the manuscript.

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