Reelin Together with ApoER2 Regulates Interneuron Migration in the Olfactory Bulb

Article (PDF Available)inPLoS ONE 7(11):e50646 · November 2012with32 Reads
DOI: 10.1371/journal.pone.0050646 · Source: PubMed
One pathway regulating the migration of neurons during development of the mammalian cortex involves the extracellular matrix protein Reelin. Reelin and components of its signaling cascade, the lipoprotein receptors ApoER2 and Vldlr and the intracellular adapter protein Dab1 are pivotal for a correct layer formation during corticogenesis. The olfactory bulb (OB) as a phylogenetically old cortical region is known to be a prominent site of Reelin expression. Although some aspects of Reelin function in the OB have been described, the influence of Reelin on OB layer formation has so far been poorly analyzed. Here we studied animals deficient for either Reelin, Vldlr, ApoER2 or Dab1 as well as double-null mutants. We performed organotypic migration assays, immunohistochemical marker analysis and BrdU incorporation studies to elucidate roles for the different components of the Reelin signaling cascade in OB neuroblast migration and layer formation. We identified ApoER2 as being the main receptor responsible for Reelin mediated detachment of neuroblasts and correct migration of early generated interneurons within the OB, a prerequisite for correct OB lamination.
    • "Another important regulator of mTOR-dependent dendritogenesis in hippocampal and cortical neurons is reelin (Jossin and Goffinet, 2007; Matsuki et al., 2008). Since reelin is also expressed in OB postnatally (Hellwig et al., 2012) one could speculate that reelin controls dendritogenesis of postnatally born neurons in mTOR-dependent fashion. However, thus far, there is no evidence that reelin is needed for dendritic arbor development in postnatally born OB neurons. "
    [Show abstract] [Hide abstract] ABSTRACT: Neurogenesis is the process of neuron generation, which occurs not only during embryonic development but also in restricted niches postnatally. One such region is called the subventricular zone (SVZ), which gives rise to new neurons in the olfactory bulb (OB). Neurons that are born postnatally migrate through more complex territories and integrate into fully functional circuits. Therefore, differences in the differentiation of embryonic and postnatally born neurons may exist. Dendritogenesis is an important process for the proper formation of future neuronal circuits. Dendritogenesis in embryonic neurons cultured in vitro was shown to depend on the mammalian target of rapamycin (mTOR). Still unknown, however, is whether mTOR could regulate the dendritic arbor morphology of SVZ-derived postnatal OB neurons under physiological conditions in vivo. The present study used in vitro cultured and differentiated SVZ-derived neural progenitors and found that both mTOR complex 1 and mTOR complex 2 are required for the dendritogenesis of SVZ-derived neurons. Furthermore, using a combination of in vivo electroporation of neural stem cells in the SVZ and genetic and pharmacological inhibition of mTOR, we found that mTOR is crucial for the growth of basal and apical dendrites in postnatally born OB neurons under physiological conditions and contributes to the stabilization of their basal dendrites. This article is protected by copyright. All rights reserved.
    Full-text · Article · Mar 2016
    • "Conversely, Reelin produced by these cells is required for interneurons to detach from the RMS and adopt their normal laminar position (Hack et al., 2002; Hellwig et al., 2012). In reeler mutants, for example, some TH + and CB + interneurons fail to reach the glomerular layer and instead reside in the external plexiform layer; some defects have also been reported in the distribution of CR + interneurons in the granular layer (Hellwig et al., 2012 ). Nevertheless, the position of PV + interneurons in the external plexiform layer, and most periglomerular interneurons, is unaffected by the loss of Reelin signaling, which suggests that the correct laminar distribution of olfactory bulb interneurons depends on additional factors . "
    [Show abstract] [Hide abstract] ABSTRACT: The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development.
    Full-text · Article · Apr 2014
    • "However, in Nestin-Cre;Tbr2 Flox/Flox animals, Tbx21 was virtually eliminated from the OB, suggesting near complete loss of mitral cells in mutant mice (Fig. 1L, arrowhead), consistent with previous reports (Arnold et al. 2008). Previous work has shown that mitral cells express Reelin, a molecule important for directing neuronal migration in the OB (Hack et al. 2002; Hellwig et al. 2012). We examined Reelin expression in the developing and postnatal OB of Tbr2 mutant mice and controls to further characterize how loss of Tbr2 impacts mitral cell development. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Development of the olfactory bulb (OB) is a complex process that requires contributions from several progenitor cell niches to generate neuronal diversity. Previous studies showed that Tbr2 is expressed during the generation of glutamatergic OB neurons in rodents. However, relatively little is known about the role of Tbr2 in the developing OB or in the subventricular zone-rostral migratory stream (SVZ-RMS) germinal niche that gives rise to many OB neurons. Results: Here, we use conditional gene ablation strategies to knockout Tbr2 during embryonic mouse olfactory bulb morphogenesis, as well as during perinatal and adult neurogenesis from the SVZ-RMS niche, and describe the resulting phenotypes. We find that Tbr2 is important for the generation of mitral cells in the OB, and that the olfactory bulbs themselves are hypoplastic and disorganized in Tbr2 mutant mice. Furthermore, we show that the SVZ-RMS niche is expanded and disordered following loss of Tbr2, which leads to ectopic accumulation of neuroblasts in the RMS. Lastly, we show that adult glutamatergic neurogenesis from the SVZ is impaired by loss of Tbr2. Conclusions: Tbr2 is essential for proper morphogenesis of the OB and SVZ-RMS, and is important for the generation of multiple lineages of glutamatergic olfactory bulb neurons.
    Full-text · Article · Mar 2014
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