Reelin Together with ApoER2 Regulates Interneuron Migration in the Olfactory Bulb

Institute of Anatomy and Cell Biology I, University of Freiburg, Freiburg, Germany.
PLoS ONE (Impact Factor: 3.23). 11/2012; 7(11):e50646. DOI: 10.1371/journal.pone.0050646
Source: PubMed

ABSTRACT 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.

  • Source
    • "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.
    Nature 04/2014; 508(7495). DOI:10.1038/nature13185 · 42.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In the forebrain, cortical structures consist of networks of excitatory and inhibitory neurons born in distant locations. Understanding how these two major classes of neurons integrate into unique functional cell assemblies may shed light on the organization of cortical circuits. In this review, we provide an overview of the mechanisms used by GABAergic interneurons to reach their final position, with an emphasis on the final steps of this process. To this end, we analyze similarities and differences between the integration of GABAergic interneurons in the developing cerebral cortex and in the postnatal brain, using the neocortex and the olfactory bulb as model systems.
    Neuron 09/2013; 79(5):849-64. DOI:10.1016/j.neuron.2013.08.014 · 15.98 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Incorrect placement of nerve cells during brain development leaves us at risk of diseases and conditions ranging from epilepsy and mental retardation to schizophrenia and dyslexia. The developing brain produces cells at an impressive rate, with up to 250,000 new cells generated every minute. These newborn cells migrate long distances in sequential waves to settle in the layers that make up the cerebral cortex. If a nerve cell moves too fast or too slow during this journey, it may not take the correct route or reach its appropriate destination. Much knowledge has been accumulated on molecular cues and transcriptional programs regulating cortical development. More recently, components of the c-Jun N-terminal signaling cascade have been brought to light as important intracellular regulators of nerve cell motility. In this chapter, we focus on this family of protein kinases, their upstream activators and downstream targets in the context of neuronal migration. We first present basic information on these molecules, much of which derives from studies outside the nervous system. We then highlight key findings on JNK signaling in brain where it phosphorylates brain-specific proteins that influence microtubule homeostasis. Finally, we summarize recent findings from transgenic mice on the regulation of neuronal migration by JNK cascade components and by JNK substrates.
    Advances in Experimental Medicine and Biology 01/2014; 800:37-57. DOI:10.1007/978-94-007-7687-6_3 · 2.01 Impact Factor
Show more