RESUMEN
Microglia, the resident myeloid cells of the central nervous system, play important roles in life-long brain maintenance and in pathology. Despite their importance, their regulatory dynamics during brain development have not been fully elucidated. Using genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development, we found that microglia undergo three temporal stages of development in synchrony with the brain--early, pre-, and adult microglia--which are under distinct regulatory circuits. Knockout of the gene encoding the adult microglia transcription factor MAFB and environmental perturbations, such as those affecting the microbiome or prenatal immune activation, led to disruption of developmental genes and immune response pathways. Together, our work identifies a stepwise microglia developmental program integrating immune response pathways that may be associated with several neurodevelopmental disorders.
Asunto(s)
Encéfalo/embriología , Homeostasis/fisiología , Microglía/citología , Neurogénesis/inmunología , Animales , Barrera Hematoencefálica/embriología , Barrera Hematoencefálica/inmunología , Encéfalo/inmunología , Cromatina/metabolismo , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Técnicas de Inactivación de Genes , Código de Histonas , Homeostasis/genética , Inmunidad/genética , Factor de Transcripción MafB/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/inmunología , Células Mieloides/citología , Neurogénesis/genética , Análisis de la Célula IndividualRESUMEN
Orthologs of the Drosophila gap gene hunchback have been isolated so far only in protostomes. Phylogenetic analysis of recently available genomic data allowed us to confirm that hunchback genes are widely found in protostomes (both lophotrochozoans and ecdysozoans). In contrast, no unequivocal hunchback gene can be found in the genomes of deuterostomes and non-bilaterians. We cloned hunchback in the marine polychaete annelid Platynereis dumerilii and analysed its expression during development. In this species, hunchback displays an expression pattern indicative of a role in mesoderm formation and neurogenesis, and similar to the expression found for hunchback genes in arthropods. These data suggest altogether that these functions are ancestral to protostomes.