In recent years, our laboratory has focused much effort on understanding the molecular and cellular mechanisms regulating muscle cell fusion. The fusion of differentiating muscle cells to existing muscle fibers is a crucial step of muscle formation and repair that is poorly understood. We have undertaken a genome-wide functional screen on a mouse muscle cell line and identified hundreds of molecules implicated in the fusion of this cell line, with no effect on their proliferation or differentiation. Inhibitors and activators of fusion, members of various signaling pathways, genes that when mutated, lead to muscle dystrophies in human: there are many surprises within this list of putative modulators of muscle fusion. To test their function during fusion, we use the chick embryo as a model. The amenability of the chick embryo to manipulation and imaging, combined with the powerful technique of in vivo electroporation and the strong similarities of muscle formation in birds and mammals provide a unique paradigm to characterize this process in amniotes.
A second line of research is to use skeletal muscle formation in the chick embryo as a model to understand how cells within tissues display complex behaviours while being exposed to an ever-changing cellular environment. We have recently shown that in avian embryos, muscle formation is initiated by Delta1-positive neural crest cells migrating from the dorsal neural tube that, in passing, trigger NOTCH signalling and myogenesis in selected epithelial somite progenitor cells, allowing them to migrate into the nascent muscle to differentiate.
Preliminary data we have now obtained further indicate that in somite cells, the activation of the NOTCH pathway triggers a "signalling module" that couples the initiation of myogenesis with the epithelial-mesenchymal transition (EMT) that allows them to migrate into the growing muscle. This is a significant discovery: in many cellular contexts, essential cell fate decisions are associated with an EMT. This is true at many stages of embryonic development (e.g. the formation of the three germ layers during gastrulation, the formation of neural crest, etc.), but also during pathologies like the metastatic progression of carcinomas. Inhibiting EMT arrests cell fate decision in these experimental models, suggesting a mechanistic link between both processes that has never been understood. Our working hypothesis is that the signalling module we have uncovered underlies the coupling cell fate changes to EMT in a variety of developmental and pathological processes.
Chicken embryo at 5.5 days of development, clarified by the "3DISCO" technique, observed with a Z1 light sheet confocal microscope (Zeiss, CIQLE platform).
Green: neural crest and peripheral nervous system (anti-HNK1); Blue: dermomyotome, muscle progenitors and dorsal neural tube (anti-PAX7); Red: differentiated muscles (anti-Myosin Heavy Chain).
Marie-Julie Dejardin, Marcelle group
- CRISPR/Cas9 in the chicken embryo
Morin V., Véron N., Marcelle C. Methods Molecular Biology (2017) 1650:113-123.
- Cytoplasmic NOTCH and membrane derived β-catenin link fate choice to epithelial-mesenchymal transition during myogenesis
Sieiro D., Rios A.C., Hirst C.E., Marcelle C. Elife (2016) 5. pii: e14847.
- The avian embryo as a model system for skeletal myogenesis
Hirst C.E., Marcelle C. Results Probl Cell Differ. (2015) 56:99-122.
- CRISPR mediated somatic cell genome engineering in the chicken
Véron N., Qu Z., Kipen P., Hirst C.E., Marcelle C. Developmental Biology (2015) 407: 68-74.
- A dynamic analysis of muscle fusion in the chick embryo
Sieiro-Mosti D., De La Celle M., Pele M., Marcelle C. Development (2014) 141: 3605-3611.
- Migrating cells mediate long-range WNT signaling
Serralbo O., Marcelle C. Development (2014) 141: 2057-2063.
- Neural crest regulates myogenesis through the transient activation of Notch
Rios AC., Serralbo O., Salgado D., Marcelle C. Nature (2011) 473:532-535.
- Wnt11 acts as a directional cue to organize the elongation of early muscle fibers
Gros J., Serralbo O., Marcelle C. Nature (2009) 457:589-93.
- Myostatin promotes the terminal differentiation of embryonic muscle progenitors
Manceau M., Savage K., Gros J., Thome V., McPherron A., Paterson B., Marcelle C. Genes and Development (2008) 22 : 668-681.
- A Common Somitic Origin for Embryonic Muscle Progenitors and Satellite cells
Gros J., Manceau M., Thome V., Marcelle C. Nature (2005) 435: 954-958.
- A two step mechanism for myotome formation in chick
Gros J., Scaal M., Marcelle C. Developmental Cell. (2004) 6: 875-882.