Reprogramming Axial Level Identity to Rescue Neural-Crest-Related Congenital Heart Defects
Abstract
The cardiac neural crest arises in the hindbrain, then migrates to the heart and contributes to critical structures, including the outflow tract septum. Chick cardiac crest ablation results in failure of this septation, phenocopying the human heart defect persistent truncus arteriosus (PTA), which trunk neural crest fails to rescue. Here, we probe the molecular mechanisms underlying the cardiac crest's unique potential. Transcriptional profiling identified cardiac-crest-specific transcription factors, with single-cell RNA sequencing revealing surprising heterogeneity, including an ectomesenchymal subpopulation within the early migrating population. Loss-of-function analyses uncovered a transcriptional subcircuit, comprised of Tgif1, Ets1, and Sox8, critical for cardiac neural crest and heart development. Importantly, ectopic expression of this subcircuit was sufficient to imbue trunk crest with the ability to rescue PTA after cardiac crest ablation. Together, our results reveal a transcriptional program sufficient to confer cardiac potential onto trunk neural crest cells, thus implicating new genes in cardiovascular birth defects.
Additional Information
© 2020 Elsevier Inc. Received 2 October 2019, Revised 7 February 2020, Accepted 6 April 2020, Available online 4 May 2020. We thank Drs. Tatjana Sauka-Spengler and Megan Martik for helpful discussions. For technical assistance, we thank Jamie Tijerina and Rochelle Diamond with the Beckman Institute (BI) Flow Cytometry Facility, Igor Antoshechkin with the Jacobs Genetics and Genomics Laboratory, Giada Spigolon and Andres Collazo with the BI Biological Imaging Facility, and Fan Gao with the BI Bioinformatics Resource Center. We thank Neil Ashley and Ivan Candido Ferreira at the Weatherall Institute (University of Oxford) for help with scRNA-seq library preparation and sequencing. This work was supported by NIH grants R01DE027568 and R01HL14058 to M.E.B. and AHA predoctoral fellowship 18PRE34050063 and Company of Biologists traveling fellowship DEVTF18119 to S.G. Author Contributions: Conceptualization, S.G. and M.E.B.; Methodology, S.G. and M.E.; Software, S.G.; Validation, S.G; Formal Analysis, S.G.; Investigation, S.G. and M.E.; Writing – Original Draft, S.G., M.E., and M.E.B.; Writing – Review & Editing, S.G. and M.E.B.; Visualization, S.G.; Supervision, M.E.B.; Funding Acquisition, M.E.B. The authors declare no competing interests.Attached Files
Accepted Version - nihms-1588541.pdf
Supplemental Material - 1-s2.0-S1534580720302720-mmc1.pdf
Supplemental Material - 1-s2.0-S1534580720302720-mmc2.xlsx
Supplemental Material - 1-s2.0-S1534580720302720-mmc3.xlsx
Files
Additional details
- PMCID
- PMC7255058
- Eprint ID
- 102994
- Resolver ID
- CaltechAUTHORS:20200505-080826421
- R01DE027568
- NIH
- R01HL14058
- NIH
- 18PRE34050063
- American Heart Association
- DEVTF18119
- Company of Biologists
- Created
-
2020-05-05Created from EPrint's datestamp field
- Updated
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2023-07-18Created from EPrint's last_modified field
- Caltech groups
- Division of Biology and Biological Engineering