Is-4: Mechanisms on Arealization and Cell-Type Specification in The Developing Mammalian Neocortex

Alfano Ch *, Harb K , Magrinelli E , Elganfoud N , Studer M ,


Corticogenesis involves the formation of six distinct layers and of functionally specialized areas characterized by specific sets of pyramidal neurons with distinctive morphologies, connectivity, and developmental programs of gene expression. We have previously shown that the transcriptional regulator COUP-TFI is required in balancing the neocortex into motor and sensory areas by regulating a genetic program leading to the correct differentiation of deep layer pyramidal neurons. We have now demonstrated that COUP-TFI controls areal identity and cell-type specification at the post-mitotic level. When COUP-TFI function is abolished solely in early post-mitotic neurons by leaving its expression in progenitors unaffected, the primary and secondary motor areas, normally confined to the frontal cortex, expand to the occipital pole at the almost full expense of sensory areas. The transcriptional code specific for each cortical sub-population is altered in the absence of COUP-TFI function. In particular, expression of the LIM-homeodomain-related gene Lmo4 is highly upregulated in layers IV and V, while the bHLH transcription factor Bhlhb5 is downregulated in the same layers of the mutant somatosensory cortex. An increased number of pyramidal tract (PT)-type corticostriatal neurons is generated at the expense of the intratelencephalic (IT)- types in layer V of COUP-TFI mutant brains resulting in abnormal corticostriatal connectivity. Our study emphasizes the fundamental role of COUP-TFI in controlling areal and laminar identity by regulating expression of cell-type specific determinant genes at the post-mitotic level.