COUP-TFI is required for the formation of commissural projections in the forebrain by regulating axonal growth

Abstract

The transcription factor COUP-TFI (NR2F1), an orphan member of the nuclear receptor superfamily, is an important regulator of neurogenesis, cellular differentiation and cell migration. In the forebrain, COUP-TFI controls the connectivity between thalamus and cortex and neuronal tangential migration in the basal telencephalon. Here, we show that COUP-TFI is required for proper axonal growth and guidance of all major forebrain commissures. Fibres of the corpus callosum, the hippocampal commissure and the anterior commissure project aberrantly and fail to cross the midline in COUP-TFI null mutants. Moreover, hippocampal neurons lacking COUP-TFI have a defect in neurite outgrowth and show an abnormal axonal morphology. To search for downstream effectors, we used microarray analysis and showed that, in the absence of COUP-TFI, expression of various cytoskeleton molecules involved in neuronal morphogenesis is affected. Diminished protein levels of the microtubule-associated protein MAP1B and increased levels of the GTP-binding protein RND2 were confirmed in the developing cortex in vivo and in primary hippocampal neurons in vitro. Therefore, based on morphological studies, gene expression profiling and primary cultured neurons, the present data uncover a previously unappreciated intrinsic role for COUP-TFI in axonal growth in vivo and supply one of the premises for COUP-TFI coordination of neuronal morphogenesis in the developing forebrain.

COUP-TFI promotes radial migration and proper morphology of callosal projection neurons by repressing Rnd2 expression

“…In this study, we found that in the absence of COUP-TFI (Nr2f1 -Mouse Genome Informatics), a transcription factor crucial for corticogenesis and arealization (Armentano et al, 2006;Armentano et al, 2007;Tomassy et al, 2010), Rnd2 expression is abnormally high in the SVZ and IZ during glia-guided radial migration. As a consequence, a greater number of MSCs are stalled in the IZ and BSC migration to the CP is impaired.…”

Loss of COUP-TFI Alters the Balance between Caudal Ganglionic Eminence- and Medial Ganglionic Eminence-Derived Cortical Interneurons and Results in Resistance to Epilepsy

“…Thus, in the absence of COUP-TFI function, this repression is released and an excess of PVϩ interneurons is produced. Since COUP-TFI is expressed in the MGE from E10.5 to E12.5 (Armentano et al, 2006(Armentano et al, , 2007this study), and production of PVϩ interneurons occurs from E9.5 to E15.5 (Miyoshi et al, 2007), it is reasonable to assume that presumptive PVϩ cells express COUP-TFI while proliferating and that COUP-TFI normally controls early SVZ progenitor divisions during generation of PVϩ interneurons.…”

Transcription factors COUP-TFI and COUP-TFII are required for the production of granule cells in the mouse olfactory bulb

“…An expanded SVZ observed in the COUP-TF single and double conditional mutants may directly result from the accumulation of DCX+ immature neuroblasts, and CR+ and NeuN+ mature neurons. However, because most excitatory projection neurons in the neocortex also lost COUP-TFI expression, which can lead to the changes in cortical area patterning and altered axonal projections (Zhou et al, 1999(Zhou et al, , 2001Armentano et al, 2006Armentano et al, , 2007Faedo et al, 2008;Borello et al, 2014), these phenotypes may also indirectly result in an expanded SVZ.…”