A Hox-TALE regulatory circuit for neural crest patterning is conserved across vertebrates
Abstract
In jawed vertebrates (gnathostomes), Hox genes play an important role in patterning head and jaw formation, but mechanisms coupling Hox genes to neural crest (NC) are unknown. Here we use cross-species regulatory comparisons between gnathostomes and lamprey, a jawless extant vertebrate, to investigate conserved ancestral mechanisms regulating Hox2 genes in NC. Gnathostome Hoxa2 and Hoxb2 NC enhancers mediate equivalent NC expression in lamprey and gnathostomes, revealing ancient conservation of Hox upstream regulatory components in NC. In characterizing a lamprey hoxα2 NC/hindbrain enhancer, we identify essential Meis, Pbx, and Hox binding sites that are functionally conserved within Hoxa2/Hoxb2 NC enhancers. This suggests that the lamprey hoxα2 enhancer retains ancestral activity and that Hoxa2/Hoxb2 NC enhancers are ancient paralogues, which diverged in hindbrain and NC activities. This identifies an ancestral mechanism for Hox2 NC regulation involving a Hox-TALE regulatory circuit, potentiated by inputs from Meis and Pbx proteins and Hox auto-/cross-regulatory interactions.
Additional Information
© 2019 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 05 December 2018; Accepted 26 February 2019; Published 13 March 2019. We thank Dorit Hockman, Tetsuto Miyashita, and Megan Martik for lamprey husbandry assistance, the Stowers Institute aquatics facility for zebrafish care, and Histology facility for sectioning assistance. This study was conducted in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the NIH and protocols approved by the Institutional Animal Care and Use Committees of the Stowers Institute (Zebrafish, RK Protocol: #2015-0149), California Institute of Technology (lamprey, MEB Protocol: #1436-11), and the veterinary office of UZH and the Canton of Zürich. K.D.P., C.H., and C.M. were supported by Science Foundation (SNSF) professorship (C.M. grant 170623), a Marie Curie Career Integration Grant from the European Commission (C.M. grant PCIG14-GA-2013-631984), the Swiss Cancer League, and the Canton of Zürich. H.J.P., B.D.K., L.M.W., and R.K. were supported by the Stowers Institute (R.K. grant #2013-1001). S.A.G. and M.E.B. were supported by grants R01NS086907 and R01DE017911. Data availability: The authors declare that all data supporting the findings of this study are available within the article and its supplementary information files or from the corresponding author upon reasonable request. All raw sequencing data from this study underlying Fig. 7a have been deposited in the NCBI BioProject database [https://www.ncbi.nlm.nih.gov/bioproject] under accession code PRJNA341679 and Sequence Read Archive under accession code SRP079975 and PRJNA503882. Original data underlying this manuscript can be accessed from the Stowers Original Data Repository at [http://odr.stowers.org/websimr/]. A reporting summary for this Article is available as a Supplementary Information file. Author Contributions: H.J.P., M.E.B. and R.K. conceived this research programme. H.J.P., B.D.K., K.D.P. and C.H. conducted the experiments. S.A.G. performed lamprey husbandry. C.K.K. and C.M. developed the crestin transgenic zebrafish line and associated constructs. H.J.P., B.D.K., C.M., L.M.W., M.E.B. and R.K. analysed the data, discussed the ideas and interpretations, and wrote the manuscript. The authors declare no competing interests.Attached Files
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Additional details
- PMCID
- PMC6416258
- Eprint ID
- 93763
- Resolver ID
- CaltechAUTHORS:20190313-093703542
- 170623
- Swiss National Science Foundation (SNSF)
- PCIG14-GA-2013-631984
- Marie Curie Fellowship
- Swiss Cancer League
- Canton of Zürich
- RK 2013-1001
- Stowers Institute for Medical Research
- R01NS086907
- NIH
- R01DE017911
- NIH
- Created
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2019-03-13Created from EPrint's datestamp field
- Updated
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2022-03-01Created from EPrint's last_modified field