RESUMO
The rapid elimination of dying neurons and nonfunctional synapses in the brain is carried out by microglia, the resident myeloid cells of the brain. Here we show that microglia clearance activity in the adult brain is regionally regulated and depends on the rate of neuronal attrition. Cerebellar, but not striatal or cortical, microglia exhibited high levels of basal clearance activity, which correlated with an elevated degree of cerebellar neuronal attrition. Exposing forebrain microglia to apoptotic cells activated gene-expression programs supporting clearance activity. We provide evidence that the polycomb repressive complex 2 (PRC2) epigenetically restricts the expression of genes that support clearance activity in striatal and cortical microglia. Loss of PRC2 leads to aberrant activation of a microglia clearance phenotype, which triggers changes in neuronal morphology and behavior. Our data highlight a key role of epigenetic mechanisms in preventing microglia-induced neuronal alterations that are frequently associated with neurodegenerative and psychiatric diseases.
Assuntos
Encéfalo/fisiologia , Epigênese Genética/fisiologia , Microglia/fisiologia , Animais , Apoptose/genética , Morte Celular/genética , Cerebelo/citologia , Córtex Cerebral/citologia , Córtex Cerebral/fisiologia , Feminino , Regulação da Expressão Gênica/genética , Ativação de Macrófagos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neostriado/citologia , Neostriado/fisiologia , Neostriado/ultraestrutura , Neurônios/fisiologia , Neurônios/ultraestrutura , Complexo Repressor Polycomb 2/genética , Convulsões/genética , Sinapses/fisiologiaRESUMO
Normal brain function depends on the interaction between highly specialized neurons that operate within anatomically and functionally distinct brain regions. Neuronal specification is driven by transcriptional programs that are established during early neuronal development and remain in place in the adult brain. The fidelity of neuronal specification depends on the robustness of the transcriptional program that supports the neuron type-specific gene expression patterns. Here we show that polycomb repressive complex 2 (PRC2), which supports neuron specification during differentiation, contributes to the suppression of a transcriptional program that is detrimental to adult neuron function and survival. We show that PRC2 deficiency in striatal neurons leads to the de-repression of selected, predominantly bivalent PRC2 target genes that are dominated by self-regulating transcription factors normally suppressed in these neurons. The transcriptional changes in PRC2-deficient neurons lead to progressive and fatal neurodegeneration in mice. Our results point to a key role of PRC2 in protecting neurons against degeneration.
Assuntos
Inativação Gênica , Degeneração Neural/genética , Complexo Repressor Polycomb 2/metabolismo , Animais , Morte Celular/genética , Sobrevivência Celular/genética , Regulação para Baixo , Feminino , Histona-Lisina N-Metiltransferase/metabolismo , Masculino , Camundongos , Camundongos Knockout , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Complexo Repressor Polycomb 2/deficiência , Complexo Repressor Polycomb 2/genéticaRESUMO
Oncogenic activating mutations in NOTCH1 occur in more than 50% of T-cell acute lymphoblastic leukemias (T-ALLs). In the present study, we describe a novel mechanism of NOTCH1 activation in T-ALL in which a deletion removing the 5' portion of NOTCH1 abolishes the negative regulatory control of the extracellular domain and leads to constitutively active NOTCH1 signaling. Polypeptides translated from truncated transcripts encoded by the NOTCH1 deletion allele retain the transmembrane domain of the receptor and are constitutively cleaved by the γ-secretase complex, resulting in high levels of NOTCH1 signaling that can be effectively blocked by γ-secretase inhibitors. Our results expand the spectrum of oncogenic lesions activating NOTCH1 signaling in human T-ALL.