Postmitotic control of sensory area specification during neocortical development

Abstract

The mammalian neocortex is subdivided into cytoarchitectural areas with distinct connectivity, gene expression and neural functions. Areal identity is initially specified by rostrocaudal and mediolateral gene expression gradients in neuroepithelial and radial glial progenitors (the 'protomap'). On further differentiation, distinct sets of gene expression gradients arise in intermediate progenitors and postmitotic neurons, and are necessary to implement areal specification. However, it is still unknown whether postmitotic gene expression gradients can determine areal identity independently of protomap gradients. Here we show, by cell type-restricted genetic loss-and gain-of-function, that high levels of postmitotic COUP-TFI (Nr2f1) expression are necessary and sufficient for the development of sensory (caudal) areal identity. Our data indicate a crucial role for postmitotic patterning genes in areal specification and reveal an unexpected plasticity in this process, which may account for complex and evolutionarily novel structures characteristic of the mammalian neocortex.

Molecular control of two novel migratory paths for CGE-derived interneurons in the developing mouse brain

“…We also found that COUP-TFI acts on the LMS population expressing SP8 and on the MMS population expressing COUP-TFII. The regulation of COUP-TFI on Sp8 expression has been well documented in the cortex (Alfano et al, 2014b;Borello et al, 2014), and control of COUP-TFI on COUP-TFII expression levels has been recently shown in the hippocampus (Flore et al, 2016). Thus, a similar mechanism in the CGE might limit the cohort of LMS SP8 + cells reaching the cortex, and compensate for the lack of COUP-TFI in the MMS, as previously proposed for the hippocampus, as both COUP-TFs have similar binding sites and could thus compete for the same target genes (Alfano et al, 2014a).…”

COUP-TFI mitotically regulates production and migration of dentate granule cells and modulates hippocampal CXCR4 expression

“…S6D,D′). To further support the role of COUP-TFI in regulating Cxcr4 expression in progenitors, we used a complementary approach by crossing the Cre-dependent hCOUP-TFI-floxed transgenic line (Alfano et al, 2014b) with Emx1-Cre, thus allowing overexpression of COUP-TFI in all hippocampal progenitors (Fig. 8G-H′).…”

“…To investigate this, the COUP-TFI flox/flox mouse line was crossed to the Nex-Cre mouse, which acts in early differentiating cortical neurons (Alfano et al, 2014b;Goebbels et al, 2006) (Fig. 7A,A′).…”

“…Generation of COUP-TFI conditional and overexpressing mice, as well as the Thy1-eYFP-H line have been previously described (Alfano et al, 2014b;Armentano et al, 2007;Harb et al, 2016). Midday on the day of vaginal plug formation was considered as embryonic day 0.5 (E0.5).…”

“…Cryosections (16 µm) were processed for immunofluorescence or immunohistochemistry, as previously described (Alfano et al, 2014b) by overnight incubation at 4°C with the primary antibodies, followed by 2 h at room temperature with secondary antibodies (Table S1). Immunohistochemistry slides followed the standard avidin-biotin complex reaction procedure (Vector Laboratories), and staining was revealed using DAB Peroxidase Substrate (Vector) following the manufacturer's instructions.…”