Eliminação de neurônios infragranulares afeta a especificação de neurônios granulares e supragranulares do córtex cerebral em desenvolvimento

摘要

The cerebral cortex of mammals is histologically organized into indifferent layers of excitatory neurons that have distinct patterns of connectionswith cortical or subcortical targets. During development, these cortical layers aresequentially established through an intricate combination of neuronalspecification and migration in a radial pattern known as "inside-out": deep-layerneurons are generated prior to upper-layer neurons. In the last few decades,several genes encoding transcription factors involved in the specification ofneurons destined to different cortical layers have been identified. However, theinfluence of early-generated neurons in to the specification of subsequentneuronal cohorts remains unclear. To investigate the possible effects early bornneurons ablation on the specification of late born neurons, we induced theselective death of cortical neurons from layers V and VI neurons before thegeneration of neurons destined to layers II, III and IV. Our data shows that onedayafter ablation, progenitors resumed generation of layer VI neuronsexpressing the transcription factor TBR1, whereas virtually no TBR1-expressingneuron was generated at the same developmental stage in age-matchedcontrols. Interestingly, many TBR1-positive neurons generated after deep-layerablation settled within superficial cortical layers, as expected for upper-layerneurons generated at that stage, suggesting that migration post-mitotic neuronsis independent of fate-specification. Furthermore, we observed an increase inlayer V neurons expressing CTIP2 and cortico-cortical neurons expressingSATB2 at the expense of layer IV neurons in P0 animals. When these animalsbecame young adults (P30) the increase os SATB2 and CTIP2 neurons is nolonger observed, however these neurons are distributed in a different way insomatosensory areas from ablated animals. In vitro experiments show that thelaminar cytoarchitectural organization of the cortex is necessary to regeneratethe previously deleted TBR1 + neurons. In addition, in vitro experimentsindicate that in a condition of low cell density the neurons phnotype is altered,they express several transcription factors at the same time. Together, our dataindicate the existence of feedback mechanism either from early-generatedneurons to progenitors involved in the generation of upper-layer neurons orfrom deep-layer neurons to postmitotic neurons generated subsequently. Thismechanism could help to control the number of neurons in different layers andcontribute to the establishment of different cortical areas.