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Crosstalk between the myotome and muscle stem cells during the development of the skeletal muscles of the back

Publication . Gonçalves, André Brás; Thorsteinsdóttir, Sólveig; Deries, Marianne

The deep back (or epaxial) muscles of amniotes derive from the transient myotomes, segmented embryonic muscles that develop from the delamination and differentiation of muscle stem cells (MuSCs) from the overlying dermomyotome. During embryonic development, myogenesis is ensured by the activation of key transcription factors: Myf5, Mrf4, MyoD and Myogenin. The main goal of this thesis was to investigate the role of the myotome in epaxial muscle development. In Chapter 2, a technique of culturing mouse embryo explants was developed, which allowed us to study the in vivo ex utero development of the epaxial myotome and its extracellular matrix (ECM). In Chapter 3, we analysed to what extent the myotome is necessary for later epaxial muscle development using the Myf5nlacZ/nlacZ mouse line, in which the absence of Myf5 and Mrf4 results in the lack of an early myotome. We show that one specific epaxial muscle group (the transversospinalis) is able to differentiate through MyoD, while the other three epaxial muscle groups fail to form. Moreover, we show that due to the lack of myotomal factors, the maintenance of the identity of delaminating dermomyotomal MuSCs fails. In Chapter 4, we described the organisation of laminins, fibronectin and tenascin-C ECMs during myotome development showing that each one of these ECMs potentially has a specific spatial relationship with MuSCs. Finally, Chapter 5 focuses on the role of the myotome in the organisation of these same ECMs and its role in tendon development, using Myf5nlacZ/nlacZ mouse embryos. We show that the myotome is necessary to assemble its own matrices, but these are not required for the development of the transversospinalis muscles. The results of this thesis suggest that the transversospinalis muscles have a distinct developmental mechanism from that of the remaining epaxial muscles and we propose that they are evolutionary more recent.

2019-07Doctoral thesis

Open access

Dynamics of laminin niches during muscle development and disease

Publication . Nunes, Andreia Marcelino, 1988-; Thorsteinsdóttir, Sólveig, 1962-; Deries, Marianne

The development of skeletal and cardiac muscles are complex processes which start early in embryogenesis. Skeletal muscle cells of the trunk, limbs and tongue arise from the somite-derived dermomyotome. The myotome, the first differentiated skeletal muscle, is formed when the dermomyotome precursors enter the myogenic program and delaminate from the dermomyotome. Following stages of skeletal muscle development are marked by the formation of the embryonic and fetal myofibers. Cardiac muscle development starts when the cardiogenic progenitors in the splanchnic mesoderm are brought to the midline to form the heart tube. The heart tube then undergoes several developmentally regulated rearrangements, originating the four cardiac chambers and a myocardium capable of pumping the blood. The main goal of this thesis was the characterization of laminin niches during muscle development. In chapter 2 and 3, we addressed the dynamics of laminin synthesis and assembly during skeletal muscle development. Our results reveal a complex assembly dynamics, which generate specific microenvironments during different phases of muscle development. We then focused our analysis on the role of laminin niches during the onset of the Merosin deficient congenital muscular dystrophy type 1A (MDC1A) in the dyW mouse model, and demonstrated that absence of laminin 211 in the myofiber basement membrane leads to impaired fetal muscle growth. In Chapter 4 we show the progress in the development of different techniques to unveil the mechanism by which laminin 211 signals during skeletal muscle development. In Chapter 5, we characterized the dynamics of laminin assembly during cardiac development and found that different phases of cardiac development are marked by specific laminin niches. Together, the results presented in this thesis provide a detailed framework on laminin matrices during muscle development. This thesis also unveils an important role of laminin 211 during the fetal development of skeletal muscles.

2017Doctoral thesis

Open access