ORCID Profile
0000-0001-5750-5163
Current Organisation
Brigham and Women's Hospital
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Publisher: The Company of Biologists
Date: 15-09-2014
DOI: 10.1242/DEV.114546
Abstract: Skeletal muscle development, growth and regeneration depend upon the ability of muscle cells to fuse into multinucleated fibers. Surprisingly little is known about the cellular events that underlie fusion during amniote development. Here, we have developed novel molecular tools to characterize muscle cell fusion during chick embryo development. We show that all cell populations arising from somites fuse, but each with unique characteristics. Fusion in the trunk is slow and independent of fiber length. By contrast, the addition of nuclei in limb muscles is three times more rapid than in trunk and is tightly associated with fiber growth. A complex interaction takes place in the trunk, where primary myotome cells from the medial somite border rarely fuse to one another, but readily do so with anterior and posterior border cells. Conversely, resident muscle progenitors actively fuse with one another, but poorly with the primary myotome. In summary, this study unveils an unexpected variety of fusion behaviors in distinct embryonic domains that is likely to reflect a tight molecular control of muscle fusion in vertebrates.
Publisher: BMJ
Date: 31-10-2016
DOI: 10.1136/JMEDGENET-2016-104259
Abstract: The underlying molecular aetiology of congenital heart defects is largely unknown. The aim of this study was to explore the genetic basis of non-syndromic severe congenital valve malformations in two unrelated families. Whole-exome analysis was used to identify the mutations in five patients who suffered from severe valvular malformations involving the pulmonic, tricuspid and mitral valves. The significance of the findings was assessed by studying sporulation of yeast carrying a homologous Phospholipase D ( Three mutations, p.His442Pro, p.Thr495fs32* and c.2882+2T>C, were identified in the The findings support a role for PLD1 in normal heart valvulogenesis.
Publisher: Cold Spring Harbor Laboratory
Date: 29-10-2020
DOI: 10.1101/2020.10.29.360826
Abstract: Duchenne Muscular Dystrophy (DMD) is a devastating genetic disease leading to degeneration of skeletal muscles and premature death. How dystrophin absence leads to muscle wasting remains unclear. Here, we describe an optimized protocol to differentiate human induced Pluripotent Stem Cells (iPSC) to a late myogenic stage. This allows to recapitulate classical DMD phenotypes (mislocalization of proteins of the Dystrophin-glycoprotein associated complex (DGC), increased fusion, myofiber branching, force contraction defects and calcium hyperactivation) in isogenic DMD-mutant iPSC lines in vitro . Treatment of the myogenic cultures with prednisolone (the standard of care for DMD) can dramatically rescue force contraction, fusion and branching defects in DMD iPSC lines. This argues that prednisolone acts directly on myofibers, challenging the largely prevalent view that its beneficial effects are due to anti-inflammatory properties. Our work introduces a new human in vitro model to study the onset of DMD pathology and test novel therapeutic approaches.
Publisher: eLife Sciences Publications, Ltd
Date: 24-05-2016
DOI: 10.7554/ELIFE.14847
Abstract: How cells in the embryo coordinate epithelial plasticity with cell fate decision in a fast changing cellular environment is largely unknown. In chick embryos, skeletal muscle formation is initiated by migrating Delta1-expressing neural crest cells that trigger NOTCH signaling and myogenesis in selected epithelial somite progenitor cells, which rapidly translocate into the nascent muscle to differentiate. Here, we uncovered at the heart of this response a signaling module encompassing NOTCH, GSK-3β, SNAI1 and β-catenin. Independent of its transcriptional function, NOTCH profoundly inhibits GSK-3β activity. As a result SNAI1 is stabilized, triggering an epithelial to mesenchymal transition. This allows the recruitment of β-catenin from the membrane, which acts as a transcriptional co-factor to activate myogenesis, independently of WNT ligand. Our results intimately associate the initiation of myogenesis to a change in cell adhesion and may reveal a general principle for coupling cell fate changes to EMT in many developmental and pathological processes.
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.YDBIO.2017.08.025
Abstract: The migration of limb myogenic precursors from limb level somites to their ultimate site of differentiation in the limb is a paradigmatic ex le of a set of dynamic and orchestrated migratory cell behaviours. The homeobox containing transcription factor ladybird homeobox 1 (Lbx1) is a central regulator of limb myoblast migration, null mutations of Lbx1 result in severe disruptions to limb muscle formation, particularly in the distal region of the limb in mice (Gross et al., 2000). As such Lbx1 has been hypothesized to control lateral migration of myoblasts into the distal limb anlage. It acts as a core regulator of the limb myoblast migration machinery, controlled by Pax3. A secondary role for Lbx1 in the differentiation and commitment of limb musculature has also been proposed (Brohmann et al., 2000 Uchiyama et al., 2000). Here we show that lateral migration, but not differentiation or commitment of limb myoblasts, is controlled by the phosphorylation of three adjacent serine residues of LBX1. Electroporation of limb level somites in the chick embryo with a dephosphomimetic form of Lbx1 results in a specific defect in the lateral migration of limb myoblasts. Although the initial delamination and migration of myoblasts is unaffected, migration into the distal limb bud is severely disrupted. Interestingly, myoblasts undergo normal differentiation independent of their migratory status, suggesting that the differentiation potential of hypaxial muscle is not regulated by the phosphorylation state of LBX1. Furthermore, we show that FGF8 and ERK mediated signal transduction, both critical regulators of the developing limb bud, have the capacity to induce the phosphorylation of LBX1 at these residues. Overall, this suggests a mechanism whereby the phosphorylation of LBX1, potentially through FGF8 and ERK signalling, controls the lateral migration of myoblasts into the distal limb bud.
Publisher: Public Library of Science (PLoS)
Date: 16-05-2017
No related grants have been discovered for Daniel Sieiro Mosti.