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.
Highlights
The olfactory bulb (OB) is a phylogenetically old cortical region, which like the neocortex is laminated and consists of five individual layers: glomerular layer (GL), external plexiform layer (EPL), mitral cell layer (MCL), internal plexiform layer (IPL) and granule cell layer (GCL)
Expression of Reelin, apolipoprotein E receptor 2 (ApoER2), Vldlr and disabled 1 (Dab1) in the OB We analyzed mRNA expression of Reelin and components of its signaling pathway in the OB by semi-quantitative RT-PCR at different developmental time points (P0, P7, P14 and adult)
Western immunoblotting analysis confirmed the presence of Vldlr protein in the adult OB of wild-type mice (Fig. 1C).To study the corresponding expression patterns, we performed immunohistochemistry for Reelin and in situ hybridization experiments for ApoER2, Vldlr and Dab1 on sagittal brain sections of early postnatal (P0) and adult wild-type mice
Summary
The OB is a phylogenetically old cortical region, which like the neocortex is laminated and consists of five individual layers: glomerular layer (GL), external plexiform layer (EPL), mitral cell layer (MCL), internal plexiform layer (IPL) and granule cell layer (GCL) These layers are formed in an inside-outside manner during development [1]. Interneurons have been shown to arise from the lateral ganglionic eminence and dorsal telencephalon [9,10,11,12,13,14] whereas postnatally interneurons derive from the anterior part of the subventricular zone (SVZ) of the lateral ventricle [15,16,17,18] From this neurogenic region, precommitted neuroblasts migrate tangentially in a chain-like organization into the OB, forming the rostral migratory stream (RMS). The interaction of radial migrating cells with their environment and the molecular signals underlying and regulating this process are as yet poorly understood (reviewed in [19])
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