Gradient COUP-TFI Expression Is Required for Functional Organization of the Hippocampal Septo-Temporal Longitudinal Axis

Abstract

The hippocampus (HP), a medial cortical structure, is subdivided into a distinct dorsal (septal) and ventral (temporal) portion, which is separated by an intermediate region lying on a longitudinal curvature. While the dorsal portion is more dedicated to spatial navigation and memory, the most ventral part processes emotional information. Genetic factors expressed in gradient during development seem to control the size and correct positioning of the HP along its longitudinal axis; however, their roles in regulating differential growth and in supporting its anatomical and functional dissociation remain unexplored. Here, we challenge the in vivo function of the nuclear receptor COUP-TFI (chicken ovalbumin upstream promoter transcription factor 1) in controlling the hippocampal, anatomical, and functional properties along its longitudinal axis. Loss of cortical COUP-TFI function results in a dysmorphic HP with altered shape, volume, and connectivity, particularly in its dorsal and intermediate regions. Notably, topographic inputs from the entorhinal cortex are strongly impaired in the dorsal portion of COUP-TFI mutants. These severe morphological changes are associated with selective spatial learning and memory impairment. These findings identify a novel transcriptional regulator required in the functional organization along the hippocampal septo-temporal axis supporting a genetic basis of the hippocampal volumetric growth with its final shape, circuit, and type of memory function.

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

“…2E,E′,I), in which its septal region is 51% smaller than the control (Fig. S1A), in line with the selective hippocampal reduction we have previously described (Flore et al, 2017). By P7, the total volume of the mutant DG is decreased to 68% of its normal size ( Fig.…”

“…In this study, we unravel for the first time a key function of the transcriptional regulator COUP-TFI in DG development. We have previously shown that COUP-TFI is required for proper growth and morphogenesis of the hippocampal septal pole and its connectivity to the entorhinal cortex (Flore et al, 2017), but the origin and mechanisms of these defects have not been elucidated. Here, we show that COUP-TFI is highly expressed in the dentate primordium and maintained in all precursors during migration and differentiation, thus representing one of the few transcription factors expressed throughout all stages of DG morphogenesis.…”

“…We have recently demonstrated that the nuclear receptor COUP-TFI (or Nr2f1), which acts as a strong transcriptional regulator (Alfano et al, 2014a), is required for proper hippocampal growth and function (Flore et al, 2017). COUP-TFI mutant mice possess a hypomorphic hippocampus, specifically altered in its septal/dorsal pole, and are afflicted by a selective spatial memory deficit (Flore et al, 2017).…”

“…COUP-TFI mutant mice possess a hypomorphic hippocampus, specifically altered in its septal/dorsal pole, and are afflicted by a selective spatial memory deficit (Flore et al, 2017). However, the cellular and molecular causes of this growth defect are not known.…”

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).…”