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Reprogramming axial level identity to rescue neural crest-related
congenital heart defects
Shashank Gandhi
1
,
Max Ezin
2
,
Marianne E. Bronner
1,3,*
1
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA
91125, USA
2
Department of Biology, Loyola Marymount University, Los Angeles, CA 90045
3
Lead Contact
Summary:
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-seq 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.
Graphical Abstract
*
Correspondence: mbronner@caltech.edu.
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.
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Declaration of Interests: The authors declare no competing interests.
HHS Public Access
Author manuscript
Dev Cell
. Author manuscript; available in PMC 2021 May 04.
Published in final edited form as:
Dev Cell
. 2020 May 04; 53(3): 300–315.e4. doi:10.1016/j.devcel.2020.04.005.
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eTOC blurb:
Here, Gandhi et al. identify a molecular subcircuit comprised of transcription factors
Sox8, Tgif1
,
and
Ets1
that confers cardiac neural crest cells with their unique ability to contribute to the heart.
Moreover, expression of this subcircuit is sufficient to reprogram trunk neural crest cells to adopt a
cardiac crest-like identity.
Keywords
cardiac neural crest; heart development; aorticopulmonary septum; persistent truncus arteriosus;
outflow tract
Introduction
The vertebrate heart arises from cells in the lateral plate mesoderm that converge at the
embryonic midline and fuse into a heart tube. In amniotes, cells from the second heart field
are added after the heart tube loops, causing remodeling of the tube to form four heart
chambers—two atria and two ventricles. The looped heart connects to the forming lungs by
means of the truncus arteriosus, which initially is a single vessel destined to form the
outflow tract of the heart. Cardiac neural crest cells make a critical contribution to the heart
by septating the truncus arteriosus into the pulmonary trunk, through which deoxygenated
blood flows to the lungs, and the aortic trunk, through which oxygenated blood is pumped
throughout the body. In fact, abnormal cardiac crest development results in some of the most
Gandhi et al.
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