Muscle loves company

pon differentiation, many cell types no longer proliferate in response to growth factor–activated MAPK. But MAPK has more than just mitogenic effects, and the cells must still activate and respond to MAPK to adjust lipid metabolism, protein synthesis, and other cellular functions. On page 689, Smith et al. identify a simple, yet until now elusive, mechanism by which cells uncouple MAPK's proliferative effects from its other functions. The strategy is based on compartmentalization. To bring about cell division, MAPK phosphorylates nuclear substrates such as Elk-1. But its nonproliferation substrates are cytoplasmic. So the simple fix to stop division in differentiated cells, as Smith and colleagues show, is to prevent MAPK from entering the nucleus. The group uses retinoic acid to induce differentiation in both embryonic stem cells and an embryonic carcinoma cell line. After treatment, activated MAPK—which had resided in both the nucleus and cytoplasm of undifferentiated cells—was restricted to the cytoplasm, as were its phosphorylated substrates. Since nuclear export is not required for this change in localization, MAPK import must be blocked somehow. An intact cytoskeleton is required for the nuclear exclusion, so the authors speculate that differentiation changes actin and microtubule dynamics and cellular trafficking such that MAPK is continually transported away from nuclear pores. ᭿ U Active MAPK (green) is excluded from the nucleus (red) after differentiation (right). Muscle loves company uture muscle cells recruit more cells to their cause, according to Gerhart et al. on page 739. The group has isolated a pool of cells from the embryonic epiblast that seems to be committed even before gastrulation to form skeletal muscle. These cells express mRNA for the MyoD transcription factor and form skeletal MyoD Ϫ epiblast cells form skeletal muscle (red) if the BMP pathway is blocked. F muscle in vitro if dissociated from other epiblast cells. Muscle formation in vitro requires a switch in expression from E-to N-cadherin, which also occurs as epiblast cells undergo gastrulation in vivo. If separated from the muscle precursors, cells lacking MyoD retained E-cadherin and did not make muscle. However, when the MyoD Ϫ cells were treated with medium from the muscle precursors, they expressed N-cadherin and formed skeletal muscle. BMP-4 was able to block this inductive effect, and inhibition of the BMP receptor in MyoD Ϫ cells stimulated muscle formation. This suggests that the muscle precursors secrete a BMP antagonist, possibly Noggin, which recruits more cells to the muscle …