A tissue-specific, Gata6-driven transcriptional program instructs remodeling of the mature arterial tree
- University of Manchester, United Kingdom
- University of Massachusetts Medical School, United States
- Instituto Gulbenkian de Ciência, Portugal
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
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ChIP-seq for Meis on mouse branchial arches at E11.5Publicly available at EBI.
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Reinstatement of developmental stage-specific GATA4 enhancers controls the gene expression program in heart diseaseGata4 ChIP-seqPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE52123).
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Gene bivalency at Polycomb domains regulates cranial neural crest positional identity [ATAC-seq]ATAC-seq BA2Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE89436).
Article and author information
Author details
Charles Sagerström
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
© 2017, Losa et al.
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.
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A tissue-specific, Gata6-driven transcriptional program instructs remodeling of the mature arterial tree
eLife 6:e31362.
https://doi.org/10.7554/eLife.31362
Further reading
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- Developmental Biology
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Niches are often found in specific positions in tissues relative to the stem cells they support. Consistency of niche position suggests that placement is important for niche function. However, the complexity of most niches has precluded a thorough understanding of how their proper placement is established. To address this, we investigated the formation of a genetically tractable niche, the Drosophila Posterior Signaling Center (PSC), the assembly of which had not been previously explored. This niche controls hematopoietic progenitors of the lymph gland (LG). PSC cells were previously shown to be specified laterally in the embryo, but ultimately reside dorsally, at the LG posterior. Here, using live-imaging, we show that PSC cells migrate as a tight collective and associate with multiple tissues during their trajectory to the LG posterior. We find that Slit emanating from two extrinsic sources, visceral mesoderm and cardioblasts, is required for the PSC to remain a collective, and for its attachment to cardioblasts during migration. Without proper Slit-Robo signaling, PSC cells disperse, form aberrant contacts, and ultimately fail to reach their stereotypical position near progenitors. Our work characterizes a novel example of niche formation and identifies an extrinsic signaling relay that controls precise niche positioning.
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- Developmental Biology
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