MYF-5 AND MYOD GENES ARE ACTIVATED IN DISTINCT MESENCHYMAL STEM-CELLSAND DETERMINE DIFFERENT SKELETAL-MUSCLE CELL LINEAGES

Targeted inactivation of the myogenic determination genes myf-5 and my oD in mice resulted in moderate (Myf-5) or no muscle phenotypes (MyoD) and double knock-out mutants lacking both genes failed to develop any skeletal muscle, In order to determine the mechanism of this apparent genetic redundancy we investigated the basis of functional overlap be tween the two genes, Here we demonstrate that Myf-5 and MyoD are not e xpressed within the same muscle precursor cell, but rather determine d ifferent muscle cell lineages arising from independently committed ste m cell populations, Selective ablation of Myf-5-expressing muscle prec ursors from differentiating ES cells does not prevent MyoD-dependent m uscle cell differentiation. The early muscle progenitor cells which no rmally express Myf-5 do not develop into later appearing MyoD cells, e ven when the myf-5 gene has been inactivated, Thus skeletal musculatur e in vertebrates develops from two separate cell lineages and compleme ntation mag occur at the cellular level, but not between different myo genic factor genes within one cell.