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

Abstract

Development of the dentate gyrus (DG), the primary gateway for hippocampal inputs, spans embryonic and postnatal stages, and involves complex morphogenetic events. We have previously identified the nuclear receptor COUP-TFI as a novel transcriptional regulator in the postnatal organization and function of the hippocampus. Here, we dissect its role in DG morphogenesis by inactivating it in either granule cell progenitors or granule neurons. Loss of COUP-TFI function in progenitors leads to decreased granule cell proliferative activity, precocious differentiation and increased apoptosis, resulting in a severe DG growth defect in adult mice. COUP-TFI-deficient cells express high levels of the chemokine receptor Cxcr4 and migrate abnormally, forming heterotopic clusters of differentiated granule cells along their paths. Conversely, high COUP-TFI expression levels downregulate Cxcr4 expression, whereas increased Cxcr4 expression in wild-type hippocampal cells affects cell migration. Finally, loss of COUP-TFI in postmitotic cells leads to only minor and transient abnormalities, and to normal Cxcr4 expression. Together, our results indicate that COUP-TFI is required predominantly in DG progenitors for modulating expression of the Cxcr4 receptor during granule cell neurogenesis and migration.

Mouse Nr2f1 haploinsufficiency unveils new pathological mechanisms of a human optic atrophy syndrome

“…The mouse Nr2f1 and human NR2F1 proteins are very well conserved during evolution and share 98–100% of sequence homology in both DBDs and LBDs (Bertacchi et al , ). Nr2f1 is widely and dynamically expressed in several mouse brain regions (Wang et al , ; Qiu et al , ; Tripodi et al , ; Armentano et al , ; Lodato et al , ; Alfano et al , ; Flore et al , ; Parisot et al , ; Bertacchi et al , ), and its expression pattern seems to be well conserved in human embryos and fetuses, as recently shown (Alzu'bi et al , ,b). Thus, structural and expression similarities between mouse and humans strongly suggest a conserved role of NR2F1 during development of the central nervous system (CNS).…”

“…Since Nr2f1 promotes cell differentiation in different regions of the CNS (Faedo et al, 2008;Lodato et al, 2011a;Parisot et al, 2017;Bertacchi et al, 2018), we asked whether partial or complete loss of Nr2f1 function in the NR would affect cell proliferation and/or RGC differentiation ( Fig 2J-V). Retinal neurons start to be generated around E11.5 in the mouse eye and express the neuron-specific btubulin marker Tuj1 and the RGC marker Brn3a (Heavner & Pevny, 2012).…”

Neuron-Astroglia Cell Fate Decision in the Adult Mouse Hippocampal Neurogenic Niche Is Cell-Intrinsically Controlled by COUP-TFI In Vivo

“…COUP-TFI (also called NR2F1) is a nuclear hormone receptor acting as a strong transcriptional regulator whose functions range from the control of embryonic NSC behavior (Naka-Kaneda et al, 2014;Naka et al, 2008) to the regulation of cell migration in the neocortex and developing DG (Alfano et al, 2011;Bertacchi et al, 2018;Parisot et al, 2017). Cortical depletion of COUP-TFI during early stages results in abnormal motor skill behavior and spatial memory deficits (Flore et al, 2016;Tomassy et al, 2010), and haploinsufficiency of COUP-TFI in patients leads to global developmental delay, intellectual disabilities, and optic atrophy (Al-Kateb et al, 2013;Bosch et al, 2014;Bertacchi et al, 2018).…”

Reelin Mediates Hippocampal Cajal-Retzius Cell Positioning and Infrapyramidal Blade Morphogenesis

“…The mechanism by which CTR-truncated RELN mediates abnormal positioning of the Cajal-Retzius cells is not obvious. Potential mechanisms involved could be altered CXCR4-CXCL12 signaling (Bagri et al, 2002;Lu et al, 2002;Li et al, 2009;Hodge et al, 2013;Parisot et al, 2017), and an abnormal contact-mediated repulsion, which was shown to be mediated by Eph/ephrin signaling (Villar-Cervino et al, 2013).…”