T-box transcription factors and their roles in regulatory hierarchies in the developing heart

Stennard, Fiona A.; Harvey, Richard P.

doi:10.1242/dev.02099

Cited by 147 publications

(120 citation statements)

References 137 publications

(174 reference statements)

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“…7) (Martin and Kimelman, 2008). We therefore place Tbx16 together with Tbx20 as T-box factors that are known to be dualfunction activators/repressors (Stennard and Harvey, 2005).…”

Section: Tbx16 Is a Dual-function Activator/repressormentioning

confidence: 99%

Wnt signaling andtbx16form a bistable switch to commit bipotential progenitors to mesoderm

et al. 2015

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Anterior to posterior growth of the vertebrate body is fueled by a posteriorly located population of bipotential neuro-mesodermal progenitor cells. These progenitors have a limited rate of proliferation and their maintenance is crucial for completion of the anterior-posterior axis. How they leave the progenitor state and commit to differentiation is largely unknown, in part because widespread modulation of factors essential for this process causes organism-wide effects. Using a novel assay, we show that zebrafish Tbx16 (Spadetail) is capable of advancing mesodermal differentiation cell-autonomously. Tbx16 locks cells into the mesodermal state by not only activating downstream mesodermal genes, but also by repressing bipotential progenitor genes, in part through a direct repression of sox2. We demonstrate that tbx16 is activated as cells move from an intermediate Wnt environment to a high Wnt environment, and show that Wnt signaling activates the tbx16 promoter. Importantly, high-level Wnt signaling is able to accelerate mesodermal differentiation cellautonomously, just as we observe with Tbx16. Finally, because our assay for mesodermal commitment is quantitative we are able to show that the acceleration of mesodermal differentiation is surprisingly incomplete, implicating a potential separation of cell movement and differentiation during this process. Together, our data suggest a model in which high levels of Wnt signaling induce a transition to mesoderm by directly activating tbx16, which in turn acts to irreversibly flip a bistable switch, leading to maintenance of the mesodermal fate and repression of the bipotential progenitor state, even as cells leave the initial highWnt environment.

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“…7) (Martin and Kimelman, 2008). We therefore place Tbx16 together with Tbx20 as T-box factors that are known to be dualfunction activators/repressors (Stennard and Harvey, 2005).…”

Section: Tbx16 Is a Dual-function Activator/repressormentioning

confidence: 99%

Wnt signaling andtbx16form a bistable switch to commit bipotential progenitors to mesoderm

et al. 2015

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“…In Drosophila, the protein Midline, which belongs to the T-box family of transcription factors (Stennard and Harvey, 2005), controls the transcription of Robo and Slit along the midline of the central and peripheral nervous systems (Liu et al, 2009). Interestingly, Midline has orthologues in other species, such as Tbx20 in the mouse (Liu et al, 2009).…”

Section: Transcriptional Regulationmentioning

confidence: 99%

Moving away from the midline: new developments for Slit and Robo

2010

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SummaryIn most tissues, the precise control of cell migration and cellcell interaction is of paramount importance to the development of a functional structure. Several families of secreted molecules have been implicated in regulating these aspects of development, including the Slits and their Robo receptors. These proteins have well described roles in axon guidance but by influencing cell polarity and adhesion, they participate in many developmental processes in diverse cell types. We review recent progress in understanding both the molecular mechanisms that modulate Slit/Robo expression and their functions in neural and non-neural tissue. Key words: Axon guidance, Cell migration, Cell-cell interaction IntroductionIn most organisms, the central nervous system (CNS) develops along a bilateral axis of symmetry located at the midline (Placzek and Briscoe, 2005). During development, the ventral midline or floor plate acts as an organiser through the secretion of diffusible proteins (Placzek and Briscoe, 2005;Gore et al., 2008), which control the growth of axons and dendrites and the migration of neurons across the midline. In the forebrain, glial or neuronal cells delineate the midline (see Glossary, Box 1) and also control axon guidance. For more than two decades, many developmental neurobiologists have tried to understand the mechanisms that control midline crossing in the CNS and to answer some key questions. Firstly, how are commissural axons (see Glossary, Box 1) attracted to the midline and how do their growth cones (see Glossary, Box1) receive and integrate the multiple and contrasting signals released by midline cells? Secondly, what are the molecular and signalling changes that enable commissural axons to leave the midline and often to switch to a longitudinal growth mode? All midline-derived axon guidance factors are expressed at other locations in many developing and mature tissues, where they control a wide range of biological processes.Roundabout receptors (Robo) and their Slit ligands form one of the most crucial ligand-receptor pairings among the axon guidance molecules. Robos were identified in Drosophila in a mutant screen for genes that control the midline crossing of commissural axons (Kidd et al., 1998;Seeger et al., 1993). Similarly, Slit was discovered in Drosophila as a protein secreted by midline glia (Rothberg et al., 1988;Rothberg et al., 1990). Homologues of both proteins have since been discovered in many species (for a review, see . However, the Slit/Robo couple not only functions in axon guidance but also in a variety of developmental Development 137, 1939Development 137, -1952Development 137, (2010 Commissural axons Axons with cell bodies (somata) located on one side of the central nervous system (CNS) that project axons across the midline to contact target cells on the opposite side. Growth cone A specialised bulbous enlargement at the end of growing axons that is characterised by dynamic filamentous extensions, known as filopodia. They sense the environment and respond to adhesi...

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“…43,44 Tbx2 is critically involved in the repression of chamber-specific gene expression in the AVC in mouse and fish. [15][16][17][18]45 Our data suggest that Tbx2 is expressed strongly in the developing AVC, steeply tapering off toward the embryonic ventricle.…”

Section: A Model For Chamber Formation From Primary Myocardiummentioning

confidence: 99%

The Tbx2 ⁺ Primary Myocardium of the Atrioventricular Canal Forms the Atrioventricular Node and the Base of the Left Ventricle

Aanhaanen

Brons

Domínguez³

et al. 2009

Circulation Research

156

182

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Abstract-The primary myocardium of the embryonic heart, including the atrioventricular canal and outflow tract, is essential for septation and valve formation. In the chamber-forming heart, the expression of the T-box transcription factor Tbx2 is restricted to the primary myocardium. To gain insight into the cellular contributions of the Tbx2 ϩ primary myocardium to the components of the definitive heart, genetic lineage tracing was performed using a novel Tbx2 Cre allele. These analyses revealed that progeny of Tbx2 ϩ cells provide an unexpectedly large contribution to the Tbx2-negative ventricles. Contrary to common assumption, we found that the embryonic left ventricle only forms the left part of the definitive ventricular septum and the apex. The atrioventricular node, but not the atrioventricular bundle, was found to derive from Tbx2 ϩ cells. The Tbx2 ϩ outflow tract formed the right ventricle and right part of the ventricular septum. In Tbx2-deficient embryos, the left-sided atrioventricular canal was found to prematurely differentiate to chamber myocardium and to proliferate at increased rates similar to those of chamber myocardium. As a result, the atrioventricular junction and base of the left ventricle were malformed. Together, these observations indicate that Tbx2 temporally suppresses differentiation and proliferation of primary myocardial cells. A subset of these Tbx2Cre -marked cells switch off expression of Tbx2, which allows them to differentiate into chamber myocardium, to initiate proliferation, and to provide a large contribution to the ventricles. These findings imply that errors in the development of the early atrioventricular canal may affect a much larger region than previously anticipated, including the ventricular base. Key Words: atrioventricular canal Ⅲ lineage Ⅲ fate Ⅲ patterning Ⅲ transgenic Ⅲ Cre T he embryonic heart tube is composed of "primary" myocardium and rapidly elongates by addition of progenitor cells to its poles. During looping, specific regions in the embryonic tubular heart differentiate to chamber myocardium and expand to form the future working myocardium of the ventricles and atria. In contrast, the region in between these expanding chambers does not differentiate or expand and becomes visible as an atrioventricular constriction. 1 During prenatal life, the atrioventricular canal (AVC) myocardium conducts the electric impulse between the atrial and ventricular chambers in a slow manner, reminiscent of the function of the mature atrioventricular (AV) node. This slow conducting feature allows the AVC to act as a sphincter preventing backflow from the ventricles to the atria, analogous to the AV valves. Furthermore, the primary myocardium provides the signals that initiate formation of the cushions, which subsequently will form the valves and partake in septation. 2,3 The primary myocardial AVC is extensively remodeled to properly connect and align both atria and ventricles and to coordinate the formation of the fibrous insulation. 4 Given all these roles of the AV...

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T-box transcription factors and their roles in regulatory hierarchies in the developing heart

Cited by 147 publications

References 137 publications

Wnt signaling andtbx16form a bistable switch to commit bipotential progenitors to mesoderm

Wnt signaling andtbx16form a bistable switch to commit bipotential progenitors to mesoderm

Moving away from the midline: new developments for Slit and Robo

The Tbx2 ⁺ Primary Myocardium of the Atrioventricular Canal Forms the Atrioventricular Node and the Base of the Left Ventricle

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T-box transcription factors and their roles in regulatory hierarchies in the developing heart

Cited by 147 publications

References 137 publications

Wnt signaling andtbx16form a bistable switch to commit bipotential progenitors to mesoderm

Wnt signaling andtbx16form a bistable switch to commit bipotential progenitors to mesoderm

Moving away from the midline: new developments for Slit and Robo

The Tbx2 + Primary Myocardium of the Atrioventricular Canal Forms the Atrioventricular Node and the Base of the Left Ventricle

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The Tbx2 ⁺ Primary Myocardium of the Atrioventricular Canal Forms the Atrioventricular Node and the Base of the Left Ventricle