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Two groups at the Institut Pasteur in association with the CNRS (French National Scientific Research Centre) have called into question a 10-year-old paradigm by showing that three genetic factors, and not two as commonly believed, determine skeletal muscle identity from stem cells. This work, published on September 23rd in Nature, changes our view of the determination of muscle cells, and of the acquisition of cellular identity in general. In the short term, by understanding the mechanisms that regulate the transition of stem cells to muscle cells, this work will allow for better strategies involving gene and cellular therapy for myopathies.
How does a stem cell, with the potential to adopt different fates, give rise to cartilage, muscle or skin cell? In order to address this question, and understand which factors determine the final fate of a stem cell, skeletal muscle is considered to be an excellent example. Indeed, in the absence of factors which determine muscle identity, muscle stem cells remain multipotent and can develop, under the influence of other factors, into dermal or cartilage cells (1).
For over ten years, it was commonly believed that only two genes, Myf5 and Myod, were the determining factors which orient the development of stem cells into muscle cells. Indeed, mice lacking these two genes were thought to be born without muscle fibres, and their precursors, known as myoblasts (2). This popular belief has now been called into question by the work published in Nature by two groups from the Institut Pasteur in association with the CNRS (3), the group of Shahragim Tajbakhsh (Stem Cells and Development) in collaboration with the group of Margaret Buckingham (Molecular Genetics of Development).
The researchers have demonstrated the preponderant role of a third gene, Mrf4, in determining muscle cell identity. The action of this gene, correlated to that of the gene Myf5, precedes, rather than follows, as people once believed, that of the Myod gene, in the embryo. Their findings show that it is both the chronological order in which these three factors intervene and their quantity that directs stem cells to muscle. These aspects, order, quantity, as well as site of expression, will determine whether skeletal muscles will be established in the head and body. Therefore, different genetic pathways, selectively involving the Mrf4, Myf5 and Myod genes, among others, intervene depending on the anatomical position of the muscles (head, body) and this could explain why certain myopathies specifically affect certain muscles and not others.
Using elaborate genetic constructions, the teams at the Institut Pasteur and the CNRS show that the role of the Mrf4 gene has been masked until now by the techniques used to demonstrate the role of Myf5 in mice. These techniques have unexpectedly inhibited the expression of the Mrf4 gene. "Aside from the interest that these findings provide for understanding how cellular identity is defined from stem cells," explains Shahragim Tajbakhsh, "our work sounds an alert signal, once again, for all researchers using homologous recombination. This technique, which has permitted the development of hundreds of mutant animal models, may hide the actions of other nearby genes through unexpected and unidentified effects."
These results represent a significant progress in our knowledge of the early events that lead stem cells to become skeletal muscle. They will enable scientists to refine their cellular therapy tools for myopathies, and above all, create new possibilities for gene therapy.
(1)Tajbakhsh, S., D. Rocancourt and M. Buckingham (1996). Muscle progenitor cells failing to respond to positional cues adopt non-myogenic fates in myf-5 null mice. Nature 384: 266-270.
(2) Rudnicki, M. A., Schneglesberg, P. N. J., Stead, R. H., Braun, T., Arnold, H.-H. and Jaenisch, R. (1993). MyoD or myf-5 is required for the formation of skeletal muscle. Cell 75, 1351-1359.
(3) Genetic, Cellular and Molecular Bases of Development Unit, CNRS
Mrf4 determines skeletal muscle identity in Myf5 :Myod double-mutant mice : Nature 431: 466-471. September 23, 2004.
Lina Kassar-Duchossoy (1),Barbara Gayraud-Morel (1), Danielle Gomès (1), Didier Rocancourt (2), Margaret Buckingham (2), Vasily Shinin (1) and Shahragim Tajbakhsh (1)
1. Stem Cells and Development Group, CNRS-Institut Pasteur
2. Molecular Genetics of Development Unit, CNRS-Institut Pasteur
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