The molecular switch behind muscle formation
During embryonic development – or throughout adult life, whenever it is necessary to repair a muscle injury – stem cells multiply, fuse together and differentiate to form the fibers needed to regenerate the tissue. In a study published today in Nature Communications, scientists report the discovery of the first molecular switch – a protein acting as an epigenetic regulator – that governs the process, whose malfunction is involved in many muscolar diseases, including Duchenne muscular dystrophy (DMD). The research, conducted by the group of Davide Gabellini, head of the Gene Expression and Muscular Distrophy Unit, paves the way for the development of new therapeutic strategies that can facilitate tissue regeneration.
Cell fusion is a fundamental process involved in many biological functions and has been extensively studied in muscles formation. During embryonic development or as a consequence of an injury – such as those that result from intense physical activities – muscle progenitor cells (called myoblasts) multiply and, upon migration to the damaged site, merge together to form new fibers.
Although this process – called myoblasts fusion – is thoroughly studied and well understood from a mechanistic and molecular point of view, until now very little has been known about its regulation: when and how myoblasts fusion gets activated or, on the contrary, it fails to, with pathological consequences. That is why the results obtained by Ilaria Castiglioni, postdoctoral fellow at the Gene Expression and Muscular Distrophy Unit headed by Davide Gabellini, are so relevant.
The researchers discovered that a protein called Ash1L plays a key role in the process of myoblasts fusion. Ash1L is an epigenetic activator: a protein that acts as a switch, turning on the transcription of other genes. «The involvement of Ash1L is fundamental: in mice without it, muscle development is reduced; furthermore, Ash1L expression is diminished in patients affected by Duchenne muscular dystrophy, in which skeletal muscle tissue formation is compromised», explains Davide Gabellini.
Once the correlation between the fusion process and the Ash1L expression was proven, the scientists wondered what gene gets activated by Ash1L and is required for myoblasts fusion in fibers. Using advanced genomics techniques, in collaboration with the Translational Genomics and Bioinformatics Center, and integrating the results with what is already known about the process, the group was able to identify the gene targeted by Ash1L: it’s called Cdon and plays a role in the mutual recognition and cell adhesion, both necessary for myoblasts fusion. In fact, in the absence of Cdon (or of its activator Ash1L), myoblasts are still able to duplicate, properly differentiate and migrate where needed, but they are no longer able to merge with each other.
«The study provides a better understanding of the mechanisms behind muscle formation and its failure in many muscular diseases, and it could provide new therapeutic strategies to improve current treatments by supporting myoblast fusion and fiber formation», concludes Davide Gabellini.
Ilaria Castiglioni, Roberta Caccia, Jose Manuel Garcia-Manteiga, Giulia Ferri, Giuseppina Caretti, Ivan Molineris, Kenichi Nishioka, Davide Gabellini, The Trithorax protein Ash1L promotes myoblast fusion by activating Cdon expression, Nature Communications, 9:5026