RESUMEN
Ras signaling elicits diverse outputs, yet how Ras specificity is generated remains incompletely understood. We demonstrate that Wingless (Wg) and Decapentaplegic (Dpp) confer competence for receptor tyrosine kinase-mediated induction of a subset of Drosophila muscle and cardiac progenitors by acting both upstream of and in parallel to Ras. In addition to regulating the expression of proximal Ras pathway components, Wg and Dpp coordinate the direct effects of three signal-activated (dTCF, Mad, and Pointed-functioning in the Wg, Dpp, and Ras/MAPK pathways, respectively) and two tissue-restricted (Twist and Tinman) transcription factors on a progenitor identity gene enhancer. The integration of Pointed with the combinatorial effects of dTCF, Mad, Twist, and Tinman determines inductive Ras signaling specificity in muscle and heart development.
Asunto(s)
Proteínas Bacterianas , Tipificación del Cuerpo/genética , Linaje de la Célula/genética , Proteínas de Drosophila , Transducción de Señal/genética , Factores de Transcripción/genética , Proteínas ras/genética , Proteínas ras/metabolismo , Animales , Sitios de Unión/genética , Proteínas de Unión al ADN , Drosophila/embriología , Drosophila/genética , Drosophila/metabolismo , Elementos de Facilitación Genéticos/genética , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Regulación del Desarrollo de la Expresión Génica/genética , Corazón/embriología , Proteínas de Homeodominio/genética , Proteínas de Insectos/genética , Proteínas de Insectos/metabolismo , Mesodermo/metabolismo , Músculo Esquelético/citología , Músculo Esquelético/embriología , Músculo Esquelético/metabolismo , Miocardio/citología , Miocardio/metabolismo , Proteínas del Tejido Nervioso , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Células Madre/citología , Células Madre/metabolismo , Proteína Wnt1RESUMEN
BACKGROUND: The Drosophila gene runt plays multiple roles during embryogenesis, including one as a pair-rule class segmentation gene. The runt protein (Runt) contains an evolutionarily conserved domain (the Runt domain) that is found in several mammalian proteins including the human protein AML1, which is involved in many chromosome translocations associated with leukaemia. Specific DNA binding activity of a mammalian Runt domain is enhanced by a partner protein called PEBP2beta/CBFbeta. DNA binding activity of Drosophila Runt is also stimulated by this protein, suggesting the existence of a similar Runt partner protein in Drosophila. RESULTS: We report here the cloning of two closely linked Drosophila genes, runt domain partner (rp) beta1 and beta2, that encode homologues of mouse PEBP2beta/CBFbeta. They are highly homologous to each other and to the mammalian counterpart. Either of the rpb proteins is capable of forming a complex with Runt and stimulating its DNA binding activity, but their temporal and spatial distributions are quite dissimilar, suggesting that functional specificity of Runt may be conferred by the interacting partner. Runt represses transcription dominantly when coexpressed with either partner in cultured cells, a function consistent with a direct role for Runt in regulating expression of the even-skipped gene in Drosophila embryos. CONCLUSIONS: Drosophila Runt can interact with either of two Runt domain partners, and the resulting complex functions as an active repressor of transcription.