Abstract
The hepatocyte growth factor receptor C-met plays an important role in cellular migration, which is crucial for many developmental processes as well as for cancer cell metastasis. C-met has been linked to the development of mammalian appendicular muscle, which are derived from migrating muscle progenitor cells (MMPs) from within the somite. Mammalian limbs are homologous to the teleost pectoral and pelvic fins. In this study we used Crispr/Cas9 to mutate the zebrafish met gene and found that the MMP derived musculature of the paired appendages was severely affected. The mutation resulted in a reduced muscle fibre number, in particular in the pectoral abductor, and in a disturbed pectoral fin function. Other MMP derived muscles, such as the sternohyoid muscle and posterior hypaxial muscle were also affected in met mutants. This indicates that the role of met in MMP function and appendicular myogenesis is conserved within vertebrates.
Highlights
Cellular migration is one of the corner stones of the processes that forms the structure and organisation of the multicellular organism and has important implications for development and disease
Using whole mount in situ hybridisation, we found that met expression was reduced in the fin buds of met-/- embryos 48 hours post fertilization, likely due to a combination of non-sense mediated decay and a failure of migratory muscle progenitor cells (MMPs) migration (S1 Fig). met-/- mutants could be identified already at 3 days post fertilization due to impaired pectoral fin function (S1 and S2 Movies)
The MMP cells that will form the pectoral fin musculature become divided into two dorsally and ventrally oriented clusters, which will develop into the abductor and adductor muscle respectively
Summary
Cellular migration is one of the corner stones of the processes that forms the structure and organisation of the multicellular organism and has important implications for development and disease. The migratory muscle progenitor cells (MMPs) are a group of cells which originally reside within the embryonic somite and upon inductive signals the MMPs delaminate from the somite and migrate laterally, giving rise to hypaxial muscle groups [1,2,3]. The formation of muscle cells in mammals is initiated in the presomitic mesoderm where inductive signals, such as HH and FGF from the midline and surrounding embryonic structures initiates a myogenic programme in the somites and expression of the myogenic regulatory factors (MRFs, e.g Myf, MyoD and Myogenin) results in the subsequent differentiation of muscle fibres. In the early stages of mammalian somitic compartmentalization, the transcription factor Pax is expressed throughout the mesodermal cells in the whole somite [8].
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