CHANGING LAMININ NICHES IN SKELETAL MUSCLE: DISSECTING THEIR ROLE IN DEVELOPMENT AND DISEASE

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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.

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Fundação para a Ciência e a Tecnologia

Número da atribuição

SFRH/BD/86985/2012