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Previous issue date: 2017-04-11 === O c?rtex cerebral de mam?feros ? histologicamente organizado em
diferentes camadas de neur?nios excitat?rios que possuem diversos padr?es
de conex?o com alvos corticais e subcorticais. Durante o desenvolvimento,
essas camadas corticais se estabelecem sequencialmente atrav?s de uma
intrincada combina??o de especifica??o neuronal e migra??o em um padr?o
radial conhecida como ?de dentro para fora?: neur?nios infragranulares s?o
gerados primeiro do que os neur?nios granulares e supragranulares. Nas
?ltimas d?cadas, diversos genes codificando fatores de transcri??o envolvidos
na especifica??o de neur?nios destinados a diferentes camadas corticais foram
identificados. Todavia, a influ?ncia dos neur?nios infragranulares sobre a
especifica??o das coortes neuronais subsequentes permanece pouco
entendida. Para investigar os poss?veis efeitos da abla??o de neur?nios
infragranulares sobre a especifica??o de neur?nios supragranulares, n?s
induzimos a morte seletiva de neur?nios corticais das camadas V e VI antes da
gera??o dos neur?nios destinados ?s camadas II-IV. Nossos dados revelam
que um dia ap?s a abla??o, progenitores continuaram a gerar neur?nios
destinados a camada VI que expressam o fator de transcri??o TBR1, enquanto
praticamente nenhum neur?nio expressando TBR1 foi gerado na mesma etapa
do desenvolvimento em controles com a mesma idade. Curiosamente, alguns
neur?nios TBR1-positivos gerados ap?s a abla??o de neur?nios infragranulares
se estabeleceram em camadas corticais superficiais, como esperado para
neur?nios supragranulares gerados neste est?gio, sugerindo que a migra??o
de neur?nios corticais pode ser controlada independentemente da sua
especifica??o molecular. Al?m disso, n?s observamos um aumento em
neur?nios de camada V que expressam CTIP2 e neur?nios calosos que
expressam SATB2 ? custa da diminui??o neur?nios de camada IV em animais
P0. Quando estes animais se tornam adultos jovens (P30) o aumento de
neur?nios SATB2 e CTIP2 n?o existe mais, todavia encontramos esses
neur?nios distribu?dos de forma diferente na ?rea somatossensorial dos
animais que sofreram abla??o. Experimentos in vitro revelaram que a
organiza??o citoarquitet?nica laminar do c?rtex ? necess?ria para gerar
novamente os neur?nios TBR1+ que foram eliminados anteriormente. Al?m
disso, experimentos in vitro indicam que em condi??o de baixa densidade
celular os neur?nios tem seu fen?tipo alterado, expressando v?rios fatores de
transcri??o ao mesmo tempo. Em conjunto, nossos dados indicam a exist?ncia
de um mecanismo regulat?rio entre neur?nios infragranulares e progenitores
envolvidos na gera??o de neur?nios supragranulares e/ou entre neur?nios
infragranulares e neur?nios p?s-mit?ticos gerados em seguida. Este mecanismo poderia ajudar a controlar o n?mero de neur?nios em diferentes camadas e contribuir para o estabelecimento de diferentes ?reas corticais. === The cerebral cortex of mammals is histologically organized into in
different layers of excitatory neurons that have distinct patterns of connections
with cortical or subcortical targets. During development, these cortical layers are
sequentially established through an intricate combination of neuronal
specification and migration in a radial pattern known as "inside-out": deep-layer
neurons are generated prior to upper-layer neurons. In the last few decades,
several genes encoding transcription factors involved in the specification of
neurons destined to different cortical layers have been identified. However, the
influence of early-generated neurons in to the specification of subsequent
neuronal cohorts remains unclear. To investigate the possible effects early born
neurons ablation on the specification of late born neurons, we induced the
selective death of cortical neurons from layers V and VI neurons before the
generation of neurons destined to layers II, III and IV. Our data shows that oneday
after ablation, progenitors resumed generation of layer VI neurons
expressing the transcription factor TBR1, whereas virtually no TBR1-expressing
neuron was generated at the same developmental stage in age-matched
controls. Interestingly, many TBR1-positive neurons generated after deep-layer
ablation settled within superficial cortical layers, as expected for upper-layer
neurons generated at that stage, suggesting that migration post-mitotic neurons
is independent of fate-specification. Furthermore, we observed an increase in
layer V neurons expressing CTIP2 and cortico-cortical neurons expressing
SATB2 at the expense of layer IV neurons in P0 animals. When these animals
became young adults (P30) the increase os SATB2 and CTIP2 neurons is no
longer observed, however these neurons are distributed in a different way in
somatosensory areas from ablated animals. In vitro experiments show that the
laminar cytoarchitectural organization of the cortex is necessary to regenerate
the previously deleted TBR1 + neurons. In addition, in vitro experiments
indicate that in a condition of low cell density the neurons phnotype is altered,
they express several transcription factors at the same time. Together, our data
indicate the existence of feedback mechanism either from early-generated
neurons to progenitors involved in the generation of upper-layer neurons or
from deep-layer neurons to postmitotic neurons generated subsequently. This
mechanism could help to control the number of neurons in different layers and
contribute to the establishment of different cortical areas.
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