Divergent roles of ApoER2 and Vldlr in the migration of cortical neurons

Abstract

Reelin, its lipoprotein receptors [very low density lipoprotein receptor (Vldlr) and apolipoprotein E receptor 2 (ApoER2; also known as Lrp8)], and the cytoplasmic adaptor protein disabled 1 (Dab1) are important for the correct formation of layers in the cerebral cortex. Reeler mice lacking the reelin protein show altered radial neuronal migration resulting in an inversion of cortical layers. ApoER2 Vldlr double-knockout mutants and Dab1 mutants show a reeler-like phenotype, whereas milder phenotypes are found if only one of the two lipoprotein receptors for reelin is absent. However, the precise role of the individual reelin receptors in neuronal migration remained unclear. In the study reported here, we performed fate mapping of newly generated cortical neurons in single and double receptor mutants using bromodeoxyuridine-labeling and layer-specific markers. We present evidence for divergent roles of the two reelin receptors Vldlr and ApoER2, with Vldlr mediating a stop signal for migrating neurons and ApoER2 being essential for the migration of late generated neocortical neurons.

Ligand-induced Homotypic and Heterotypic Clustering of Apolipoprotein E Receptor 2

“…We observed strong clustering of ApoER2 by Fc-RAP, suggesting that our assay was sensitive for detecting regulated receptor clustering. We next tested F-spondin and Reelin, both of which bind to ApoER2 (11,12,19) and are important in embryonic development (2,5,6,13). Both F-spondin and Reelin induced clustering of ApoER2, a potential signaling mechanism related to the function of these molecules in the developing brain.…”

“…ApoER2 knockout mice showed that early layers of cortex were formed normally, whereas the formation of superficial late layers was affected severely. These data suggest that ApoER2 signaling plays a role in the formation of late generation neurons (5). VLDLR knockout mice showed neurons migrating in the marginal zone, suggesting that VLDLR may act as a stop signal for migrating neurons (5).…”

“…They are neuronal proteins found in synaptic compartments (3,4) that play an important role in neuronal migration during development (5,6). Knockout of either ApoER2 or VLDLR leads to relatively mild impairments in neuronal migration, but double knockouts show gross neuronal migration abnormalities in the cortex, hippocampus, and cerebellum (3,5).…”

The N-terminal region of reelin regulates postnatal dendritic maturation of cortical pyramidal neurons

“…During embryonic corticogenesis, Cajal-Retzius cells orchestrate the typical inside-out layering of the cortex by releasing the glycoprotein reelin, which is critical for neuronal migration and cell positioning by activating the very-low-density lipoprotein (VLDL) receptor and the apolipoprotein E receptor 2 (ApoER2) (1)(2)(3)(4)(5)(6). In vivo, reelin is cleaved by extracellular metalloproteinases into three fragments of which only the central fragment R3-6 is able to bind to the ApoER2 and VLDL receptors (7)(8)(9).…”

Role for Reelin in Neurotransmitter Release

“…VLDLR and ApoER2 are thought to act in a similar fashion since both receptors are able to activate the Reelin signaling cascade. However, recent studies pointed to divergent functions of ApoER2 and VLDLR in the migration of cortical neurons during brain development (Hack et al, 2007).…”