Keeping muscle cells on hold
Many of our body’s tissues carry out self-repair by calling up stem cells, which specialize to replace cells that have worn out or been injured. It is a challenge for organisms to keep a stock of stem cells on hand because left on their own, these cells usually specialize. Researchers at the MDC have now identified a molecular signal that is crucial to maintaining the generic state of cells that produce muscle. The discovery, made by Elena Vasyutina, Diana Lenhard and their colleagues in Carmen Birchmeier’s research group, has important implications for the study of muscle development and disease. Their work appears in the on-line edition of the journal PNAS.
In these images, muscle cells are highlighted with a green fluorescent marker. Samples on the left were taken from mice with an intact RBP-J protein. Red indicates satellite stem cells that produce the protein Pax7. The muscles of mice with defective RBP-J (right) are poorly developed; there are fewer cells overall, and the satellite cells have disappeared.
Embryos undergo rapid muscle-building and their stem cells are good at repairing damage. These processes slow down after birth. In adulthood, some regeneration of tissues is still possible thanks to satellite cells, an intermediate type of stem cell found at the edges of muscle fibers. Yet overall, much less muscle regeneration occurs in adults, and in some diseases there is none at all. This may be because cells are unable to specialize, but the current study shows that the opposite might also be true. If stem cells cannot be put “on hold,” they may all differentiate so quickly that the reserves run out.
Birchmeier and her colleagues knew that a protein called Notch was somehow involved in muscle development, but its role was unclear. Notch is located on the surface of cells, where it can be activated by external molecules. When this happens, a part of the protein detaches, travels into the cell nucleus, and docks onto another protein called RBP-J. This molecule acts as a sort of “gene brake” that is released by contact with Notch. The result is the activation of a wide number of genes that can change the form and behavior of cells.
The scientists wondered what would happen to muscle tissue in mice if Notch and RBP-J were unable to interact. One way to find out would be to eliminate RBP-J entirely by removing its gene, but the molecule is crucial for so many functions that embryos without it die long before they develop muscles. The solution was to create a strain of conditional knockout mice which lacked RBP-J only in muscle stem cells.
Vasyutina and Lenhard discovered that in such mice, reserves of stem cells disappear. The cells specialize wildly and too quickly. In the early embryo, they aren’t around long enough to build proper muscles; in adults, the satellite cells disappear, probably by becoming integrated into the tissue. This shows that the signal passed along by the Notch protein is crucial in setting aside a pool of cells that can be used to build muscle in embryos and repair it throughout the animal’s lifetime.
Russ Hodge
