RESUMEN
To investigate if the microRNA (miRNA) pathway is required for dendritic cell (DC) development, we assessed the effect of ablating Drosha and Dicer, the two enzymes central to miRNA biogenesis. We found that while Dicer deficiency had some effect, Drosha deficiency completely halted DC development and halted myelopoiesis more generally. This indicated that while the miRNA pathway did have a role, it was a non-miRNA function of Drosha that was particularly critical. Drosha repressed the expression of two mRNAs encoding inhibitors of myelopoiesis in early hematopoietic progenitors. We found that Drosha directly cleaved stem-loop structure within these mRNAs and that this mRNA degradation was necessary for myelopoiesis. We have therefore identified a mechanism that regulates the development of DCs and other myeloid cells.
Asunto(s)
Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Mielopoyesis/inmunología , ARN Mensajero/metabolismo , Ribonucleasa III/inmunología , Animales , Secuencia de Bases , Diferenciación Celular/genética , Diferenciación Celular/inmunología , ARN Helicasas DEAD-box/deficiencia , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/inmunología , Células Dendríticas/citología , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/metabolismo , Inflamación/inmunología , Inflamación/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/genética , MicroARNs/metabolismo , Datos de Secuencia Molecular , Mielopoyesis/genética , Cadenas Ligeras de Miosina/antagonistas & inhibidores , Cadenas Ligeras de Miosina/genética , Cadenas Ligeras de Miosina/metabolismo , Conformación de Ácido Nucleico , ARN Mensajero/química , ARN Mensajero/genética , Ribonucleasa III/deficiencia , Ribonucleasa III/genéticaRESUMEN
By genetic inactivation of key microRNA biogenesis enzymes, we and others have previously demonstrated the critical requirement of the microRNA pathway for the differentiation and function of Foxp3(+) regulatory T cells. In this study, we identified members of the miR-17 â¼ 92a cluster of microRNAs to be enriched in regulatory T cells. To investigate the function of this microRNA cluster, we deleted the gene specifically in Foxp3(+) cells in mice. We found that miR-17 â¼ 92a is required for the fitness of regulatory T cells, and deficiency impacted at the level of apoptosis and proliferation of these cells. This led to a loss of Foxp3(+) cells over time, particularly in competitive settings, and culminated in a range of immunologic perturbations. Thus, miR-17 â¼ 92a-target interactions are part of the essential microRNA networks that safeguard the regulatory T cell lineage.