A tissue-specific, Gata6-driven transcriptional program instructs remodeling of the mature arterial tree

Abstract
Data availability
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Abstract

Connection of the heart to the systemic circulation is a critical developmental event that requires selective preservation of embryonic vessels (aortic arches). However, why some aortic arches regress while others are incorporated into the mature aortic tree remains unclear. By microdissection and deep sequencing in mouse, we find that neural crest (NC) only differentiates into vascular smooth muscle cells (SMCs) around those aortic arches destined for survival and reorganization, and identify the transcription factor Gata6 as a crucial regulator of this process. Gata6 is expressed in SMCs and its target genes activation control SMC differentiation. Furthermore, Gata6 is sufficient to promote SMCs differentiation in vivo, and drive preservation of aortic arches that ought to regress. These findings identify Gata6-directed differentiation of NC to SMCs as an essential mechanism that specifies the aortic tree, and provide a new framework for how mutations in GATA6 lead to congenital heart disorders in humans.

Data availability

The following data sets were generated

1. Andrabi M
(2017) RNA-seq analysis of branchial arches and outflow tract of the mouse embryo at E10.5 and E11.5
Publicly available at EBI.

http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-5394
1. Bobola N
2. Donaldson I
(2017) ChIP-seq for Meis on mouse branchial arches at E11.5
Publicly available at EBI.

http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-5536
1. Bobola N
2. Donaldson I
(2017) ChIP-seq for Gata6 and histone H3K27Ac on mouse branchial arches at E11.5
Publicly available at EBI.

http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-5407

The following previously published data sets were used

1. He A
2. Gu F
3. Hu Y
4. Ma Q
5. Ye L
6. Visel A
7. Pennacchio LA
8. Pu WT
(2014) Reinstatement of developmental stage-specific GATA4 enhancers controls the gene expression program in heart diseaseGata4 ChIP-seq
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE52123).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE52123
1. Minoux M
2. Holwerda S
3. Vitobello A
4. Kitazawa T
5. Kohler H
6. Stadler MB
7. Rijli FM
(2017) Gene bivalency at Polycomb domains regulates cranial neural crest positional identity [ATAC-seq]ATAC-seq BA2
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE89436).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE89436

Article and author information

Author details

Marta Losa

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Victor Latorre

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Munazah Andrabi

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Franck Ladam

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States

Competing interests
The authors declare that no competing interests exist.
Charles Sagerström

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1509-5810
Ana Novoa

Instituto Gulbenkian de Ciência, Oeiras, Portugal

Competing interests
The authors declare that no competing interests exist.
Peyman Zarrineh

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Laure Bridoux

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Neil A Hanley

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3234-4038
Moises Mallo

Instituto Gulbenkian de Ciência, Oeiras, Portugal

For correspondence
mallo@igc.gulbenkian.pt

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9744-0912
Nicoletta Bobola

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

For correspondence
nicoletta.bobola@manchester.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7103-4932

Funding

Medical Research Council (MR/L009986/1)

Nicoletta Bobola

Biotechnology and Biological Sciences Research Council (BB/N00907X/1)

Nicoletta Bobola

National Institute of Neurological Disorders and Stroke (NS038183)

Charles Sagerström

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Experiments on animals followed the local (ASPA 1986, UK; Portaria 1005/92 and Directive 2010/63/EU, P) legislations concerning housing, husbandry, and welfare.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.