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Fgf-driven Tbx protein activities directly induce myf5 and myod to initiate zebrafish myogenesis.

ABSTRACT: Skeletal muscle derives from dorsal mesoderm formed during vertebrate gastrulation. Fibroblast growth factor (Fgf) signalling cooperates with Tbx transcription factors to promote dorsal mesoderm formation, but their role in myogenesis has been unclear. Using zebrafish, we show that dorsally derived Fgf signals act through Tbx16 and Tbxta to induce slow and fast trunk muscle precursors at distinct dorsoventral positions. Tbx16 binds to and directly activates the myf5 and myod genes, which are required for commitment to myogenesis. Tbx16 activity depends on Fgf signalling from the organiser. In contrast, Tbxta is not required for myf5 expression, but binds a specific site upstream of myod that is not bound by Tbx16 and drives (dependent on Fgf signals) myod expression in adaxial slow precursors, thereby initiating trunk myogenesis. After gastrulation, when similar muscle cell populations in the post-anal tail are generated from tailbud, declining Fgf signalling is less effective at initiating adaxial myogenesis, which is instead initiated by Hedgehog signalling from the notochord. Our findings suggest a hypothesis for ancestral vertebrate trunk myogenic patterning and how it was co-opted during tail evolution to generate similar muscle by new mechanisms.This article has an associated 'The people behind the papers' interview.

SUBMITTER: Osborn DPS

PROVIDER: S-EPMC7197714 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Fgf-driven Tbx protein activities directly induce myf5 and myod to initiate zebrafish myogenesis.

Osborn Daniel P S DPS Li Kuoyu K Cutty Stephen J SJ Nelson Andrew C AC Wardle Fiona C FC Hinits Yaniv Y Hughes Simon M SM

Development (Cambridge, England) 20200428 8

Skeletal muscle derives from dorsal mesoderm formed during vertebrate gastrulation. Fibroblast growth factor (Fgf) signalling cooperates with Tbx transcription factors to promote dorsal mesoderm formation, but their role in myogenesis has been unclear. Using zebrafish, we show that dorsally derived Fgf signals act through Tbx16 and Tbxta to induce slow and fast trunk muscle precursors at distinct dorsoventral positions. Tbx16 binds to and directly activates the myf5 and myod genes, ...[more]

PMID: 32345657

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Project description:The pig is an important animal model increasingly used for biomedical research, particularly in transplantation strategies involving xenotransplantation or the development of human organs in pig for exotransplantation. Pigs, however, are less characterized than other animal models. In this study, we produced wildtype (WT) pig embryos via somatic cell nuclear transfer (SCNT) technology and compared them to skeletal muscle null embryos (lacking MYF5/MYOD/MYF6) at embryonic day 41, 62, and 90, critical stages of porcine myogenesis. Magnetic resonance imaging (MRI) and histological analyses revealed progressive development of skeletal muscle in WT embryos but not in null embryos whereas development of viscera progressed equally in both groups. Molecular analyses highlighted dynamic changes in myogenic gene expression and myofiber formation, demonstrating an organized progression of myogenesis in WT embryos. Morphologically, the null embryos exhibited abnormalities, including marked edema and underdeveloped limbs. MRI revealed severe skeletal abnormalities, including the absence of ribs, sternum, and associated vertebral malformations. In addition, histological analysis confirmed the complete lack of myofiber formation. Immunohistochemical analysis revealed the absence of myogenic stem cells and muscle differentiation, and RNA sequencing demonstrated that the skeletal muscle development process was entirely disrupted in null embryos. Additionally, analysis of neuromuscular junctions (NMJs) in the null embryos revealed that functional NMJ formation was absent, consistent with the lack of skeletal muscle formation. Importantly, these defects culminated in embryonic lethality after day 62 in the null embryos. We determined that the myogenic regulatory gene cascade is crucial for porcine embryo development and viability. The deletion of skeletal muscle is essential for the creating a vacant niche to allow for complementation of null porcine embryos with human induced pluripotent stem cells. Characterization of this skeletal muscle null pig model provide an important platform for engineering humanized muscle in gene-edited pigs.

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Fgf-driven Tbx protein activities directly induce myf5 and myod to initiate zebrafish myogenesis.

Publications

Fgf-driven Tbx protein activities directly induce <i>myf5</i> and <i>myod</i> to initiate zebrafish myogenesis.

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