Tbx1 Coordinates Addition of Posterior Second Heart Field Progenitor Cells to the Arterial and Venous Poles of the Heart

Rana, M. Sameer; Théveniau-Ruissy, Magali; Bono, Christopher De; Mesbah, Karim; Francou, Alexandre; Rammah, Mayyasa; Domínguez, Jorge N.; Roux, Maurice; Laforest, Brigitte; Anderson, Robert H.; Mohun, Timothy J.; Zaffran, Stéphane; Christoffels, Vincent M.; Kelly, Robert G.

doi:10.1161/circresaha.115.305020

Cited by 114 publications

(126 citation statements)

References 49 publications

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“…More generally, our observations support the idea that a single primary genetic lesion can result in a range of OFT defects, which in clinical practice are often considered discrete entities (Dorfman and Geva, 2006;Johnson, 2010). Our data also support the idea that complex alignment phenotypes might form a continuous spectrum of related OFT alignment disorders, as others have also proposed based on observations from other mouse genetic models, particularly for Tbx1 and related pathways (Brown et al, 2004;Racedo et al, 2015;Rana et al, 2014;Vincentz et al, 2005).…”

Section: Results and Discussion Mef2c Is Required For Proper Oft Aligsupporting

confidence: 88%

MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1

et al. 2016

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Congenital heart defects are the most common birth defects in humans, and defects that affect the proper alignment of the outflow tracts and septation of the ventricles are a highly significant cause of morbidity and mortality in infants. A late differentiating population of cardiac progenitors, referred to as the anterior second heart field (AHF) gives rise to the outflow tract and the majority of the right ventricle and provides an embryological context for understanding cardiac outflow tract alignment and membranous ventricular septal defects. However, the transcriptional pathways controlling AHF development and their roles in congenital heart defects remain incompletely elucidated. Here, we inactivated the gene encoding the transcription factor MEF2C in the AHF in mice. Loss of Mef2c function in the AHF results in a spectrum of outflow tract alignment defects ranging from overriding aorta to double-outlet right ventricle and dextro-transposition of the great arteries. We identify Tdgf1, the gene that encodes the Nodal co-receptor Cripto, as a direct transcriptional target of MEF2C in the outflow tract via an AHF-restricted Tdgf1 enhancer. Importantly, both the MEF2C and TDGF1 genes are associated with congenital heart defects in humans. Thus, these studies establish a direct transcriptional pathway between the core cardiac transcription factor MEF2C and the human congenital heart disease gene TDGF1. Moreover, we found a range of outflow tract alignment defects resulting from a single genetic lesion, supporting the idea that AHF-derived outflow tract alignment defects may be an embryological spectrum rather than distinct anomalies.

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Section: Results and Discussion Mef2c Is Required For Proper Oft Aligsupporting

confidence: 88%

MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1

et al. 2016

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“…This dual origin is of major clinical importance because many heart malformations seen at birth involve this component of the arterial pole (18,19). The function of Tbx1 at both poles of the heart probably reflects its implication in this sublineage (30). Dye-I labeling of cells in cultured mouse embryos shows that some cells from the posterior part of the SHF, which is the source of myocardial cells at the venous pole of the heart, migrate anteriorly, acquire gene expression patterns typical of the anterior SHF, and contribute to outflow tract myocardium that will form the base of the pulmonary trunk (35).…”

Section: Cell Lineage Analysesmentioning

confidence: 99%

Gene regulatory networks and cell lineages that underlie the formation of skeletal muscle

Buckingham

2017

Proc. Natl. Acad. Sci. U.S.A.

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Skeletal muscle in vertebrates is formed by two major routes, as illustrated by the mouse embryo. Somites give rise to myogenic progenitors that form all of the muscles of the trunk and limbs. The behavior of these cells and their entry into the myogenic program is controlled by gene regulatory networks, where paired box gene 3 (Pax3) plays a predominant role. Head and some neck muscles do not derive from somites, but mainly form from mesoderm in the pharyngeal region. Entry into the myogenic program also depends on the myogenic determination factor (MyoD) family of genes, but Pax3 is not expressed in these myogenic progenitors, where different gene regulatory networks function, with T-box factor 1 (Tbx1) and paired-like homeodomain factor 2 (Pitx2) as key upstream genes. The regulatory genes that underlie the formation of these muscles are also important players in cardiogenesis, expressed in the second heart field, which is a major source of myocardium and of the pharyngeal arch mesoderm that gives rise to skeletal muscles. The demonstration that both types of striated muscle derive from common progenitors comes from clonal analyses that have established a lineage tree for parts of the myocardium and different head and neck muscles. Evolutionary conservation of the two routes to skeletal muscle in vertebrates extends to chordates, to trunk muscles in the cephlochordate Amphioxus and to muscles derived from cardiopharyngeal mesoderm in the urochordate Ciona, where a related gene regulatory network determines cardiac or skeletal muscle cell fates. In conclusion, Eric Davidson's visionary contribution to our understanding of gene regulatory networks and their evolution is acknowledged.skeletal myogenesis | muscle origins | second heart field | gene regulatory networks | cell lineages M ovement is a fundamental requirement for animal survival, both for finding food/feeding and for avoiding predators/ locating to a propitious environment, and depends on cells with contractile properties, mainly based on actomyosin motor activity. In more sophisticated organisms, specialized contractile proteins are present in muscle cells. In vertebrates, striated muscle permits movement and also underlies the pumping activity of the heart, which, like the simpler peristaltic pumps present in the vascular system of many animals, performs a vital function in ensuring the circulation of nutrients within the body. Striated muscles contain a range of distinct and overlapping contractile protein isoforms, adapted to functional requirements of the motor activity of different skeletal muscles or of contractility in different cardiac compartments of the heart. Although the contractile apparatus is similar at the protein level, the upstream regulation of cardiac or skeletal muscle genes is different. Skeletal muscle formation depends on myogenic regulatory factors of the myogenic determination factor (MyoD) family, whereas in cardiac muscle, these basic helix-loop-helix factors do not play a role, and other families of transcription factors...

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“…However, Tbx1 −/− embryos have recently been shown to have inflow as well as outflow tract defects, with abnormal development of the dorsal mesenchymal protrusion and impaired addition of cells to the venous pole of the heart, resulting in atrioventricular septal defects (35). Tbx1 thus regulates the behavior of cardiac progenitors that contribute to both poles of the heart tube as well as being required for the development of nonsomitic neck muscles, regulating all of the myogenic derivatives of the common lineage defined here.…”

Section: Mlc3f-2ementioning

confidence: 99%

Clonal analysis reveals a common origin between nonsomite-derived neck muscles and heart myocardium

Lescroart

Hamou

Francou

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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107

132

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Neck muscles constitute a transition zone between somite-derived skeletal muscles of the trunk and limbs, and muscles of the head, which derive from cranial mesoderm. The trapezius and sternocleidomastoid neck muscles are formed from progenitor cells that have expressed markers of cranial pharyngeal mesoderm, whereas other muscles in the neck arise from Pax3-expressing cells in the somites. Mef2c-AHF-Cre genetic tracing experiments and Tbx1 mutant analysis show that nonsomitic neck muscles share a gene regulatory network with cardiac progenitor cells in pharyngeal mesoderm of the second heart field (SHF) and branchial arch-derived head muscles. Retrospective clonal analysis shows that this group of neck muscles includes laryngeal muscles and a component of the splenius muscle, of mixed somitic and nonsomitic origin. We demonstrate that the trapezius muscle group is clonally related to myocardium at the venous pole of the heart, which derives from the posterior SHF. The left clonal sublineage includes myocardium of the pulmonary trunk at the arterial pole of the heart. Although muscles derived from the first and second branchial arches also share a clonal relationship with different SHF-derived parts of the heart, neck muscles are clonally distinct from these muscles and define a third clonal population of common skeletal and cardiac muscle progenitor cells within cardiopharyngeal mesoderm. By linking neck muscle and heart development, our findings highlight the importance of cardiopharyngeal mesoderm in the evolution of the vertebrate heart and neck and in the pathophysiology of human congenital disease.neck muscles | myocardium | retrospective clonal analysis | mouse embryo | Tbx1

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Tbx1 Coordinates Addition of Posterior Second Heart Field Progenitor Cells to the Arterial and Venous Poles of the Heart

Abstract: Tbx1 is required for inflow as well as OFT morphogenesis by regulating the segregation and deployment of progenitor cells in the posterior SHF. Our results provide new insights into the pathogenesis of congenital heart defects and 22q11.2 deletion syndrome phenotypes.

Cited by 114 publications

References 49 publications

MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1

MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1

Gene regulatory networks and cell lineages that underlie the formation of skeletal muscle

Clonal analysis reveals a common origin between nonsomite-derived neck muscles and heart myocardium

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