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

Telethon Institute of Genetics and Medicine (TIGEM), Developmental Disorders Program, 80131 Naples, Italy.
Development (Impact Factor: 6.46). 09/2011; 138(21):4685-97. DOI: 10.1242/dev.068031
Source: PubMed


During corticogenesis, late-born callosal projection neurons (CPNs) acquire their laminar position through glia-guided radial migration and then undergo final differentiation. However, the mechanisms controlling radial migration and final morphology of CPNs are poorly defined. Here, we show that in COUP-TFI mutant mice CPNs are correctly specified, but are delayed in reaching the cortical plate and have morphological defects during migration. Interestingly, we observed that the rate of neuronal migration to the cortical plate normally follows a low-rostral to high-caudal gradient, similar to that described for COUP-TFI. This gradient is strongly impaired in COUP-TFI(-/-) brains. Moreover, the expression of the Rho-GTPase Rnd2, a modulator of radial migration, is complementary to both these gradients and strongly increases in the absence of COUP-TFI function. We show that COUP-TFI directly represses Rnd2 expression at the post-mitotic level along the rostrocaudal axis of the neocortex. Restoring correct Rnd2 levels in COUP-TFI(-/-) brains cell-autonomously rescues neuron radial migration and morphological transitions. We also observed impairments in axonal elongation and dendritic arborization of COUP-TFI-deficient CPNs, which were rescued by lowering Rnd2 expression levels. Thus, our data demonstrate that COUP-TFI modulates late-born neuron migration and favours proper differentiation of CPNs by finely regulating Rnd2 expression levels.

    • "Consistent with this notion, in the present study, we first identified COUP-TFI expression mainly in a subpopulation of neural stem/progenitor cells (GFAP+ and Ascl1+) in the caudal SVZ. To our knowledge, this is the first time heterogeneity among NSCs in the rostral and caudal SVZ of the postnatal brain has been shown with respect to COUP-TFI expression, much like its expression in the embryo (Zhou et al., 2001; Faedo et al., 2008; Alfano et al., 2011; Lodato et al., 2011; Borello et al., 2014). In addition, COUP-TFI+ migratory neuroblasts (DCX+) in the SVZ and RMS, COUP-TFI+ mature interneurons in the glomerular layer and GCL of the OB were also observed (Fig. 1A) (Bovetti et al., 2013). "
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    ABSTRACT: Neural stem cells (NSCs) persist in the adult mammalian subventricular zone (SVZ) of the lateral ventricle. Primary NSCs generate rapidly dividing intermediate progenitor cells, which in turn generate neuroblasts that migrate along the rostral migratory stream (RMS) to the olfactory bulb (OB). Here, we have examined the role of the COUP-TFI and COUP-TFII orphan nuclear receptor transcription factors in mouse OB interneuron development. We observed that COUP-TFI is expressed in a gradient of low rostral to high caudal within the postnatal SVZ neural stem/progenitor cells. COUP-TFI is also expressed in a large number of migrating neuroblasts in the SVZ and RMS, and in mature interneurons in the OB. By contrast, very few COUP-TFII-expressing (+) cells exist in the SVZ-RMS-OB pathway. Conditional inactivation of COUP-TFI resulted in downregulation of tyrosine hydroxylase expression in the OB periglomerular cells and upregulation of COUP-TFII expression in the SVZ, RMS and OB deep granule cell layer. In COUP-TFI/COUP-TFII double conditional mutant SVZ, cell proliferation was increased through the upregulation of the proneural gene Ascl1. Furthermore, COUP-TFI/II-deficient neuroblasts had impaired migration, resulting in ectopic accumulation of calretinin (CR)+ and NeuN+ cells, and an increase in apoptotic cell death in the SVZ. Finally, we found that most Pax6+ and a subset of CR+ granular cells were lost in the OB. Taken together, these results suggest that COUP-TFI/II coordinately regulate the proliferation, migration and survival of a subpopulation of Pax6+ and CR+ granule cells in the OB. © 2015. Published by The Company of Biologists Ltd.
    No preview · Article · May 2015 · Development
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    • "One interpretation for this finding is that levels of Rnd2 must be finely balanced in order for cortical cells to migrate and differentiate within the E17.5 cortex. Indeed, Rnd2 is regulated by several transcription factors within the developing cortex, including COUP-TFI (Alfano et al. 2011), Neurog2 (Heng et al. 2008), and RP58. Nevertheless, we cannot rule out the possibility that other factors are also important for their " intracortical " positioning within the CP, and these may also be regulated by RP58 for their in vivo migration. "
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    ABSTRACT: The zinc finger transcription factor RP58 (also known as ZNF238) regulates neurogenesis of the mouse neocortex and cerebellum (Okado et al. 2009; Xiang et al. 2011; Baubet et al. 2012; Ohtaka-Maruyama et al. 2013), but its mechanism of action remains unclear. In this study, we report a cell-autonomous function for RP58 during the differentiation of embryonic cortical projection neurons via its activities as a transcriptional repressor. Disruption of RP58 expression alters the differentiation of immature neurons and impairs their migration and positioning within the mouse cerebral cortex. Loss of RP58 within the embryonic cortex also leads to elevated mRNA for Rnd2, a member of the Rnd family of atypical RhoA-like GTPase proteins important for cortical neuron migration (Heng et al. 2008). Mechanistically, RP58 represses transcription of Rnd2 via binding to a 3′-regulatory enhancer in a sequence-specific fashion. Using reporter assays, we found that RP58 repression of Rnd2 is competed by proneural basic helix–loop–helix transcriptional activators. Finally, our rescue experiments revealed that negative regulation of Rnd2 by RP58 was important for cortical cell migration in vivo. Taken together, these studies demonstrate that RP58 is a key player in the transcriptional control of cell migration in the developing cerebral cortex.
    Full-text · Article · Oct 2013 · Cerebral Cortex
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    • "This dramatic areal shift is neither predicted by the expression of other patterning genes, such as Pax6 and Emx2, which is only slightly altered (Armentano et al., 2007). A possible explanation of this phenotype could be derived by the impaired radial migration of neocortical neurons observed in COUP-TFI mutants (Alfano et al., 2011). This study showed that lateborn projection neurons (which will constitute layer II–IV of the cortex) reach the CP following a lowrostral to high-caudal rate of migration that is highly correlated to COUP-TFI expression. "
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    ABSTRACT: The mammalian neocortex is a structure with no equals in the vertebrates and is the seat of the highest cerebral functions, such as thoughts and consciousness. It is radially organized into six layers and tangentially subdivided into functional areas deputed to the elaboration of sensory information, association between different stimuli, and selection and triggering of voluntary movements. The process subdividing the neocortical field into several functional areas is called \arealization". Each area has its own cytoarchitecture, connectivity, and peculiar functions. In the last century, several neuroscientists have investigated areal structure and the mechanisms that have led during evolution to the rising of the neocortex and its organization. The extreme conservation in the positioning and wiring of neocortical areas among different mammalian families suggests a conserved genetic program orchestrating neocortical patterning. However, the impressive plasticity of the neocortex, which is able to rewire and reorganize areal structures and connectivity after impairments of sensory pathways, argues for a more complex scenario. Indeed, even if genetics and molecular biology helped in identifying several genes involved in the arealization process, the logic underlying the neocortical bauplan is still beyond our comprehension. In this review, we will introduce the present knowledge and hypotheses on the ontogenesis and evolution of neocortical areas. Then, we will focus our attention on some open issues, which are still unresolved, and discuss some recent studies that might open new directions to be explored in the next few years.
    Full-text · Article · Jun 2013 · Developmental Neurobiology
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