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Reprogramming Axial Level Identity to Rescue Neural-Crest-Related Congenital Heart Defects

Gandhi, Shashank and Ezin, Max and Bronner, Marianne E. (2020) Reprogramming Axial Level Identity to Rescue Neural-Crest-Related Congenital Heart Defects. Developmental Cell, 53 (3). pp. 300-315. ISSN 1534-5807. PMCID PMC7255058. doi:10.1016/j.devcel.2020.04.005. https://resolver.caltech.edu/CaltechAUTHORS:20200505-080826421

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.devcel.2020.04.005DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7255058/PubMed CentralArticle
ORCID:
AuthorORCID
Gandhi, Shashank0000-0002-4081-4338
Bronner, Marianne E.0000-0003-4274-1862
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.
Funders:
Funding AgencyGrant Number
NIHR01DE027568
NIHR01HL14058
American Heart Association18PRE34050063
Company of BiologistsDEVTF18119
Subject Keywords:cardiac neural crest; heart development; aorticopulmonary septum; persistent truncus arteriosus; outflow tract; reprogramming; specification; cardiac crest subcircuit; congenital birth defects; ectomesenchymal fate
Issue or Number:3
PubMed Central ID:PMC7255058
DOI:10.1016/j.devcel.2020.04.005
Record Number:CaltechAUTHORS:20200505-080826421
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200505-080826421
Official Citation:Shashank Gandhi, Max Ezin, Marianne E. Bronner, Reprogramming Axial Level Identity to Rescue Neural-Crest-Related Congenital Heart Defects, Developmental Cell, Volume 53, Issue 3, 2020, Pages 300-315.e4, ISSN 1534-5807, https://doi.org/10.1016/j.devcel.2020.04.005. (http://www.sciencedirect.com/science/article/pii/S1534580720302720)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102994
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:05 May 2020 15:38
Last Modified:09 Feb 2022 20:22

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