Myogenin gene disruption results in perinatal lethality because of severe muscle defect

Abstract

Myogenin is a member of the basic helix-loop-helix (bHLH) gene family and converts multipotential mesodermal cells to myoblasts. The four members of the myoD family show unique spatio-temporal expression patterns and therefore may have different functions during myogenesis. Here we inactivate the myogenin gene in order to understand its role in myogenesis. Homozygous mutations are lethal perinatally owing to the resulting major defects in skeletal muscle. The extent of disorganization of muscle tissue differs in three regions. In the latero-ventral body wall, most cells, including myogenic cells, disappear and there is rapid accretion of fluid. In the limbs, cells of the myogenic lineage exist, but they are severely disrupted, and some of them are mono-nucleate with properties of myoblasts. In contrast, there are many axial, intercostal and back muscle fibres to be seen, although fibres are mainly disorganized and Z-lines are not present in most myofibrils. These findings are evidence that myogenin is crucial for muscle development in utero and demonstrate that other members of the myogenic gene family cannot compensate for the defect.

Rhabdomyosarcoma – working out the pathways

“…For example, it is now clear that in mice MyoD and Myf-5 share redundant functions for generating myoblasts, but expression of either one or the other is essential for skeletal muscle development (Rudnicki et al, 1993). In contrast, mice with null mutations in myogenin make myoblasts, but they fail to di erentiate (Hasty et al, 1993;Nabeshima et al, 1993). Myoblasts emigrating from the medial dermomyotome defer activation of these myogenic HLH genes until after reaching their ®nal destination (Dias et al, 1994;Arnold and Braun, 1996).…”

Muscle gets stressed? p53 represses and protects

“…10 In this issue, Yang et al propose a role of p53 in the activation of the myogenic differentiation checkpoint that relies on direct repression of myogenin-a MyoD downstream target gene, whose activation is required for myoblast progression toward terminal differentiation into multinucleated myotubes. 11,12 This finding is of particular interest, when considering that in unperturbed myoblasts p53 rather seems to contribute to muscle differentiation, 13,14 as it suggests that in myoblasts the activity of p53 is biased toward inhibiting differentiation by the DNA damage signaling. The authors first discovered the transcriptional repression of myogenin by p53 in the human rhabdomyosarcoma RD cell line.…”

p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress

“…MyoD determines the myogenic lineage, whereas myogenin, a member of the MRF family, functions downstream of MyoD and plays a critical role in driving terminal differentiation as myogenin-null mice show a lethal deficiency of differentiated skeletal muscle. [8][9][10][11][12][13] The dynamic differentiation program of skeletal muscle is characterized by the orderly expression of genes and structural changes that can be recapitulated in vitro, as myogenic cells undergo cell cycle withdrawal and express early and then late differentiation genes with the formation of mononucleated myocytes to elongated multinucleated myotubes. 8,9,14 Under normal unstressed conditions, p53 has been shown to promote muscle differentiation in vitro.…”