Myogenin is required for late but not early aspects of myogenesis during mouse development.

Venuti, Judith M.; Morris, Julia Hsi; Vivian, Jay L.; Olson, Eric N.; Klein, William H.

doi:10.1083/jcb.128.4.563

Cited by 272 publications

(197 citation statements)

References 25 publications

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“…Furthermore, expression of MEF2C, a myogenic transcription factor thought to be downstream of myogenin (Cserjesi et al 1994;Edmondson et al 1994;Molkentin et al 1995), is reduced in p21 −/− p57 −m/+ animals, consistent with a defect in myogenin activity or an earlier step. The involvement of myogenin in the Rbdependent step is supported by Tedesco et al (1995), who have shown that SV40 T antigen blocks myogenesis after myogenin has been expressed, and Novitch et al (1996), who demonstrated that in the absence of Rb, MyoD induces the expression of both p21 and myogenin, but not later differentiation markers such as MHC, which depend on the function of myogenin (Hasty et al 1993;Nabeshima et al 1993;Venuti et al 1995). Whereas myogenin has been shown to interact physically with Rb in vitro, our studies do not address whether this connection is direct.…”

Section: P21 P57 and Rb Function In Muscle Development At The Myogementioning

confidence: 59%

p21CIP1 and p57KIP2 control muscle differentiation at the myogenin step

Zhang¹,

Wong²,

Liu³

et al. 1999

Genes & Development

360

332

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Cell-cycle arrest is thought to be required for differentiation of muscle cells. However, the molecules controlling cell-cycle exit and the differentiation step(s) dependent on cell-cycle arrest are poorly understood. Here we show that two Cdk inhibitors, p21 CIP1 and p57 KIP2 , redundantly control differentiation of skeletal muscle and alveoli in the lungs. Mice lacking both p21 and p57 fail to form myotubes, display increased proliferation and apoptotic rates of myoblasts, and display endoreplication in residual myotubes. This point of arrest during muscle development is identical to that of mice lacking the myogenic transcription factor myogenin, indicating a role for cell-cycle exit in myogenin function. Expression of myogenin, p21, and p57 is parallel but independent, and in response to differentiation signals, these proteins are coordinately regulated to trigger both cell-cycle exit and a dependent muscle-specific program of gene expression to initiate myoblast terminal differentiation and muscle formation. Embryonic development is a complex process that requires precise spatial and temporal control of cell proliferation coordinated together with differentiation, morphogenesis, and pattern formation. Cell proliferation in the embryo is controlled by an intricate network of signal transduction pathways that integrate growth regulatory signals through regulation of cyclin-dependent kinases (Cdks), a family of enzymes that catalyze events required for cell-cycle transitions. Primary targets for this regulation are the G 1 cyclin/Cdk complexes cyclin D/Cdk4 and cyclin E/Cdk2, which cooperate to control the G 1 → S transition through phosphorylation and inactivation of the retinoblastoma (Rb) protein. Among other functions, Rb acts as a transcriptional repressor of E2F-regulated genes important for cell proliferation (Weinberg 1995). A large number of regulatory mechanisms exist to modulate Cdk activity, reflecting the complexity of the signaling pathways involved and the necessity to precisely control proliferation for the development of an organism. A particularly versatile mechanism for developmental control is the inhibition of Cdks by cyclin-dependent kinase inhibitors (CKIs), of which there are two families: the p16 INK4a family, including p15, p16, p18, and p19; and the p21 CIP1/WAF1 family, including p21, p27, and p57 (Harper and Elledge 1996). The p16 family specifically inhibits Cdk4 and Cdk6, whereas the p21 family inhibits all Cdks involved in G 1 /S transition. The roles of these CKIs in development and in cancer have been revealed through targeted gene inactivation in mice. Although CKIs show striking tissuespecific patterns of expression during development, surprisingly only p57 loss has been shown to have a significant role in multiple tissues during embryonic development, suggesting that the other inhibitors are either not required or are redundant. Loss of p57 in humans results in the complex overgrowth and cancer predisposition disease Beckwith-Wiedemann syndrome (Zhang et al. 1997).A variety...

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Section: P21 P57 and Rb Function In Muscle Development At The Myogementioning

confidence: 59%

p21CIP1 and p57KIP2 control muscle differentiation at the myogenin step

Zhang¹,

Wong²,

Liu³

et al. 1999

Genes & Development

360

332

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“…Mice lacking myogenin possess normal numbers of skeletal myoblasts at the time of birth, but they show a severe reduction of skeletal muscle fibers (Hasty et al 1993;Nabeshima et al 1993;Venuti et al 1995). The undifferentiated myogenic cells that populate the presumptive muscle-forming regions of myogeninnull mice express MyoD and myfS, indicating that these myogenic factors act at an earlier point than myogenin in the myogenic pathway and suggesting that they cannot direct the formation of normal skeletal muscle in the absence of myogenin.…”

Section: Lvirf4-null Micementioning

confidence: 99%

“…cRNA transcripts were labeled with [3sS]UTP using an in vitro transcription kit (Stratagene) according to the manufacturer's instructions {Venuti et al 1995).…”

Section: In Situ Hybridizationmentioning

confidence: 99%

Inactivation of the myogenic bHLH gene MRF4 results in up-regulation of myogenin and rib anomalies.

Zhang¹,

Behringer²,

Olson³

1995

Genes Dev.

Self Cite

282

173

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The myogenic basic helix-loop--helix (bHLH) proteins MyoD, myf5, myogenin, and MRF4 can initiate myogenesis when expressed in nonmuscle cells. During embryogenesis, each of the myogenic bHLH genes is expressed in a unique temporospatial pattern within the skeletal muscle lineage, suggesting that they play distinct roles in muscle development. Gene targeting has shown that MyoD and myf5 play partially redundant roles in the genesis of myoblasts, whereas myogenin is required for terminal differentiation. MRF4 is expressed transiently in the somite myotome during embryogenesis and then becomes up-regulated during late fetal development to eventually become the predominant myogenic bHLH factor expressed in adult skeletal muscle. On the basis of its expression pattern, it has been proposed that MRF4 may regulate skeletal muscle maturation and aspects of adult myogenesis. To determine the function of MRF4, we generated mice carrying a homozygous germ-line mutation in the MRF4 gene. These mice showed only a subtle reduction in expression of a subset of muscle-specific genes but showed a dramatic increase in expression of myogenin, suggesting that it may compensate for the absence of MRF4 and demonstrating that MRF4 is required for the down-regulation of myogenin expression that normally occurs in postnatal skeletal muscle. Paradoxically, MRF4--null mice exhibited multiple fib anomalies, including extensive bifurcations, fusions, and supernumerary processes. These results demonstrate an unanticipated regulatory relationship between myogenin and MRF4 and suggest that MRF4 influences fib outgrowth through an indirect mechanism.

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“…Mice lacking myogenin die at birth because of a virtual absence of myofibers; however, normal numbers of MyoD-expressing myoblasts are present (Hasty et al 1993;Nabeshima et al 1993;Venuti et al 1995). In contrast, mice lacking MRF4 are viable with seemingly normal skeletal muscle but display a four-fold increase in myogenin (Patapoutian et al 1995;Zhang et al 1995).…”

Section: 1994) Newborn Mice Deficient For Both Myod Andmentioning

confidence: 99%

MyoD is required for myogenic stem cell function in adult skeletal muscle.

Megeney¹,

Kablar²,

Garrett³

et al. 1996

Genes Dev.

644

535

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To investigate the function of MyoD in adult skeletal muscle, we interbred MyoD mutant mice with mdx mice, a model for Duchenne and Becker muscular dystrophy. Mice lacking both MyoD and dystrophin displayed a marked increase in severity of myopathy leading to premature death, suggesting a role for MyoD in muscle regeneration. Examination of MyoD mutant muscle revealed elevated numbers of myogenic cells; however, myoblasts derived from these cells displayed normal differentiation potential in vitro. Following injury, MyoD mutant muscle was severely deficient in regenerative ability, and we observed a striking reduction in the in vivo proliferation of myogenic cells during regeneration. Therefore, we propose that the failure of MyoD-deficient muscle to regenerate efficiently is not caused by a reduction in numbers of satellite cells, the stem cells of adult skeletal muscle, but results from an increased propensity for stem-cell self-renewal rather than progression through the myogenic program. The myogenic regulatory factors (MRFs] form a group of basic helix-loophelix (bHLHJ transcription factors consisting of MyoD, myogenin, Myf-5, and MRF4. The MRFs are expressed exclusively in skeletal muscle, and forcing their expression in a wide range of cultured cells induces the skeletal muscle differentiation program. Therefore, these transcription factors were postulated to have a master regulatory role in the development of the skeletal muscle lineage (for review, see Weintraub et al.

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Myogenin is required for late but not early aspects of myogenesis during mouse development.

Cited by 272 publications

References 25 publications

p21CIP1 and p57KIP2 control muscle differentiation at the myogenin step

p21CIP1 and p57KIP2 control muscle differentiation at the myogenin step

Inactivation of the myogenic bHLH gene MRF4 results in up-regulation of myogenin and rib anomalies.

MyoD is required for myogenic stem cell function in adult skeletal muscle.

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