Thrombospondin-1 binds to ApoER2 and VLDL receptor and functions in postnatal neuronal migration

Abstract

Apolipoprotein E receptor 2 (ApoER2), very low-density lipoprotein receptor (VLDLR), and Dab1 are the main components of the Reelin signalling cascade. Reelin is the sole ligand defined so far in signalling through this pathway. Postnatal migration of neuronal precursors from the subventricular zone (SVZ) to the olfactory bulb (OB), however, depends on ApoER2 and Dab1, but functions independently of Reelin. Here, we show that thrombospondin-1 (THBS-1) is a novel physiological ligand for ApoER2 and VLDLR. THBS-1 is present in the SVZ and along the entire rostral migratory stream (RMS). It binds to ApoER2 and VLDLR and induces phosphorylation of Dab1. In contrast to Reelin, it does not induce Dab1 degradation or Akt phosphorylation, but stabilizes neuronal precursor chains derived from subventricular explants. Lack of THBS-1 results in anatomical abnormalities of the RMS and leads to a reduction of postnatal neuronal precursors entering the OB.

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.…”

“…F-spondin is a secreted protein involved in axonal growth (13). Both ligands have domains to induce dimerization (27,37), and both bind ApoER2 and VLDLR and activate Dab-1 phosphorylation (6,11,12,19,39,41). As above, we transfected COS-7 cells with HA-tagged and untagged ApoER2 and treated the cells for 1 h with ligand.…”

“…ApoER2 and VLDLR also bind extracellularly to a number of other molecules through ligand binding repeats in their N termini, such as apolipoprotein E (apoE) (10). One of the other extracellular ligands is F-spondin (11,12), important in axon guidance during development (13). Intracellularly, ApoER2 and VLDLR also bind several other adaptor proteins, affecting numerous downstream signals, including Src tyrosine kinases and PKB/AKT pathways (14 -18).…”

Signaling by the Extracellular Matrix Protein Reelin Promotes Granulosa Cell Proliferation in the Chicken Follicle

“…Concentrated Reelin-and mock-conditioned medium was prepared as in Ref. 29. Briefly, RCM and MCM were poured into quick-seal tubes and centrifuged overnight at 40,000 rpm in an ultracentrifuge.…”

Integration of H-2Z1, a Somatosensory Cortex-Expressed Transgene, Interferes with the Expression of theSatb1andTbc1d5Flanking Genes and Affects the Differentiation of a Subset of Cortical Interneurons

“…Downregulation of the activity-regulated cytoskeletal-associated protein (Arc), for example, could affect migration cell-autonomously. Thrombospondin1 (Thbs1) is present in the SVZ and acts as a physiological ligand of ApoER2 and VLDLR (very low-density lipoprotein receptor) (Blake et al, 2008). In the absence or decrease of Thbs1 in the SVZ, the Sstϩ cortical interneurons could respond to the superficially expressed alternative ligand Reelin resulting in a more superficial distribution.…”