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.
RNA-seq analysis of branchial arches and outflow tract of the mouse embryo at E10.5 and E11.5Publicly available at EBI.
ChIP-seq for Meis on mouse branchial arches at E11.5Publicly available at EBI.
ChIP-seq for Gata6 and histone H3K27Ac on mouse branchial arches at E11.5Publicly available at EBI.
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).
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).
- Nicoletta Bobola
- Nicoletta Bobola
- Charles Sagerström
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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.
- Marianne Bronner, California Institute of Technology, United States
© 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.
Development of tooth shape is regulated by the enamel knot signalling centre, at least in mammals. Fgf signalling regulates differential proliferation between the enamel knot and adjacent dental epithelia during tooth development, leading to formation of the dental cusp. The presence of an enamel knot in non-mammalian vertebrates is debated given differences in signalling. Here, we show the conservation and restriction of fgf3, fgf10, and shh to the sites of future dental cusps in the shark (Scyliorhinus canicula), whilst also highlighting striking differences between the shark and mouse. We reveal shifts in tooth size, shape, and cusp number following small molecule perturbations of canonical Wnt signalling. Resulting tooth phenotypes mirror observed effects in mammals, where canonical Wnt has been implicated as an upstream regulator of enamel knot signalling. In silico modelling of shark dental morphogenesis demonstrates how subtle changes in activatory and inhibitory signals can alter tooth shape, resembling developmental phenotypes and cusp shapes observed following experimental Wnt perturbation. Our results support the functional conservation of an enamel knot-like signalling centre throughout vertebrates and suggest that varied tooth types from sharks to mammals follow a similar developmental bauplan. Lineage-specific differences in signalling are not sufficient in refuting homology of this signalling centre, which is likely older than teeth themselves.
The tooth shape of sharks and mice are regulated by a similar signaling center despite their teeth having very different geometries.