RESUMEN
Satellite cells are skeletal muscle stem cells that provide myonuclei for postnatal muscle growth, maintenance, and repair/regeneration in adults. Normally, satellite cells are mitotically quiescent, but they are activated in response to muscle injury, in which case they proliferate extensively and exhibit up-regulated expression of the transcription factor MyoD, a master regulator of myogenesis. MyoD forms a heterodimer with E proteins through their basic helix-loop-helix domain, binds to E boxes in the genome and thereby activates transcription at muscle-specific promoters. The central role of MyoD in muscle differentiation has increased interest in finding potential MyoD regulators. Here we identified transducin-like enhancer of split (TLE3), one of the Groucho/TLE family members, as a regulator of MyoD function during myogenesis. TLE3 was expressed in activated and proliferative satellite cells in which increased TLE3 levels suppressed myogenic differentiation, and, conversely, reduced TLE3 levels promoted myogenesis with a concomitant increase in proliferation. We found that, via its glutamine- and serine/proline-rich domains, TLE3 interferes with MyoD function by disrupting the association between the basic helix-loop-helix domain of MyoD and E proteins. Our findings indicate that TLE3 participates in skeletal muscle homeostasis by dampening satellite cell differentiation via repression of MyoD transcriptional activity.
Asunto(s)
Proteínas Co-Represoras/metabolismo , Regulación del Desarrollo de la Expresión Génica , Desarrollo de Músculos , Fibras Musculares Esqueléticas/metabolismo , Proteína MioD/antagonistas & inhibidores , Mioblastos/metabolismo , Células Satélite del Músculo Esquelético/metabolismo , Factor de Transcripción Activador 3/química , Factor de Transcripción Activador 3/genética , Factor de Transcripción Activador 3/metabolismo , Animales , Proliferación Celular , Células Cultivadas , Proteínas Co-Represoras/antagonistas & inhibidores , Proteínas Co-Represoras/química , Proteínas Co-Represoras/genética , Eliminación de Gen , Secuencias Hélice-Asa-Hélice , Masculino , Ratones , Ratones Endogámicos C57BL , Fibras Musculares Esqueléticas/citología , Proteína MioD/química , Proteína MioD/genética , Proteína MioD/metabolismo , Mioblastos/citología , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Dominios y Motivos de Interacción de Proteínas , Multimerización de Proteína , Interferencia de ARN , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Células Satélite del Músculo Esquelético/citologíaRESUMEN
The transforming growth factor ß (TGF-ß) superfamily is a large group of signaling molecules that participate in embryogenesis, organogenesis, and tissue homeostasis. These molecules are present in all animal genomes. Dysfunction in the regulation or activity of this superfamily's components underlies numerous human diseases and developmental defects. There are 2 distinct arms downstream of the TGF-ß superfamily ligands-the bone morphogenetic protein (BMP) and activin/TGF-ß signaling pathways-and these 2 responses can oppose one another's effects, most notably in disease states. However, studies have commonly focused on a single arm of the TGF-ß superfamily, and the antagonism between these pathways is unknown in most physiologic and pathologic contexts. In this review, the authors summarize the clinically relevant scenarios in which the BMP and activin/TGF-ß pathways reportedly oppose one another and identify several molecular mechanisms proposed to mediate this interaction. Particular attention is paid to experimental findings that may be informative to human pathology to highlight potential therapeutic approaches for future investigation.