TARGETED INACTIVATION OF MYOGENIC FACTOR GENES REVEALS THEIR ROLE DURING MOUSE MYOGENESIS - A REVIEW

The role of the four myogenic regulating genes Myf-5, myogenin, MyoD, and MRF4 (herculin, Myf-6) during mouse embryogenesis has been investi gated by targeted gene inactivation. Null mutations for the MyoD gene generate no skeletal muscle phenotype due to a compensatory activation of the Myf-5 gene. Mice carrying a homozygous Myf-5 mutation exert co nsiderably delayed myotome formation with unexpected consequences. Whi le skeletal myogenesis in these mutant mice resumes normally at the on set of MyoD expression, a skeletal defect of the ribs persists. Appare ntly, Myf-5 and MyoD individually are not absolutely essential for ske letal muscle development, most likely because they have overlapping or redundant functions. In fact, double mutants lacking both, MyoD and M yf-5, fail to develop skeletal musculature and the muscle forming regi ons seem to be devoid of myoblasts. Homozygous inactivation of the myo genin gene leads to drastically reduced myofiber formation. These mice accumulate apparently normal numbers of myoblasts which are arrested in their terminal differentiation program. Myf-6 null mutant mice exhi bit drastically reduced expression of Myf-5 for reasons presently unkn own. The phenotype is very similar to Myf-5 mutants with an additional reduction of deep back muscles and minor alterations in sarcomeric pr otein isoforms. Based on the phenotypes obtained from these various ge ne ''knock-out'' mice, we now begin to understand the regulatory netwo rk and the homostatic relationship of genes which are critically invol ved in myogenesis of vertebrates.