[CITATION][C] The MyoD family and myogenesis: redundancy, networks, and thresholds

H Weintraub - Cell, 1993 - Elsevier
H Weintraub
Cell, 1993Elsevier
The members of the MyoD family of myogenic transcriptional regulators (MyoD, Myf-5,
MRF4, myogenin) have the remarkable property that, when expressed from a constitutive
promoter, they can convert a large number of different cell types into muscle (reviewed by
Buckingham, 1992; Emerson, 1990; Olson, 1990; Weintraub et al., 1991). In contrast, mice
with homozygous gene-targeted mutations in either MyoD or Myf-5 produce fairly normal
amounts of muscle (Rudnicki et al., 1992; Braun et al., 1992). This apparent paradox has …
The members of the MyoD family of myogenic transcriptional regulators (MyoD, Myf-5, MRF4, myogenin) have the remarkable property that, when expressed from a constitutive promoter, they can convert a large number of different cell types into muscle (reviewed by Buckingham, 1992; Emerson, 1990; Olson, 1990; Weintraub et al., 1991). In contrast, mice with homozygous gene-targeted mutations in either MyoD or Myf-5 produce fairly normal amounts of muscle (Rudnicki et al., 1992; Braun et al., 1992). This apparent paradox has now been resolved by two recent studies. In one, a simple genetic cross has shown that in the double homozygous mutants, in which both MyoD and Myfd are absent, no muscle is formed, no muscle markers are present, and no myogenin is transcribed (Rudnicki et al., 1993), indicating that MyoD and Myfd share an overlapping (redundant) function required for generating (or maintaining) muscle cell identity and activating myogenin. In the other study (Hasty et al., 1993; Nabeshimaet al., 1993), mice with a homozygous targeted mutation of myogenin contain myoblasts since these embryos produce normal amounts of MyoD RNA, but these cells fail to differentiate fully, indicating that myogenin has a unique function in the transition from a determined myoblast to a fully differentiated myotube. These results suggest a simple epistatic relation, shown in Figure 1. While MyoD and Myf-5 are postulated to be responsible for myoblast determination, markers for the determined myoblast state are limited; in fact, besides the expression of MyoD or Mfl-5, the only other reliable marker known is the capacity of cells to differentiate into myotubes when challenged. Thus, one wonders how MyoD and My65 actually establish a determined state, especially since known inhibitors of their transcription function (eg, Id, Jun, Myc, etc.) are present at high levels in myoblasts. Perhaps other functions of MyoD and Myf-5 define the myoblast state or perhaps the myoblast form (which is unknown) of MyoD and Myf-5 (eg, a homodimer or a heterodimer with Jun or Id) is capable of activating certain noncanonical promoters not yet identified. That there are indeed myoblast functions has now become very clear from recent knockout experiments. In myogenin knockouts, myoblasts are present in the appropriate positions and numbers in the embryo; they just fail to differentiate into muscle. However, in the MyoLIMyf-5 double knockout mice, cells fail to occupy the muscle compartments. Thus, myogenin-independent myoblast identity seems to be definable by the generation of approximately the right number of cells in the right positions of the body under the direction of MyoD-Myf-5 function. Regulation of Myogenic Genes In Vitro and In Vivo Tissue culture experiments also support the notion that
Elsevier