The low-density-lipoprotein (LDL) receptor family is an evolutionarily ancient gene family of structurally closely related cell-surface receptors. Members of the family are involved in the cellular uptake of extracellular ligands and regulate diverse biological processes including lipid and vitamin metabolism and cell-surface protease activity. Some members of the family also participate in cellular signaling and regulate the development and functional maintenance of the nervous system. Here we review the roles of this family of multifunctional receptors in the nervous system and focus on recent advances toward the understanding of the mechanisms by which lipoprotein receptors and their ligands transmit and modulate signals in the brain.

Our results show that Dab1 is a physiological substrate as well as an activator of SFKs in neurons. Based on genetic evidence gained from multiple strains of mutant mice with defects in Reelin signaling, we conclude that activation of SFKs is a normal part of the cellular Reelin response.

Reelin is a large secreted protein that controls cortical layering by signaling through the very low density lipoprotein receptor and apolipoprotein E receptor 2, thereby inducing tyrosine phosphorylation of the adaptor protein Disabled-1 (Dab1) and suppressing tau phosphorylation in vivo. Here we show that binding of Reelin to these receptors stimulates phosphatidylinositol 3-kinase, resulting in activation of protein kinase B and inhibition of glycogen synthase kinase 3␤. We present genetic evidence that this cascade is dependent on apolipoprotein E receptor 2, very low density lipoprotein receptor, and Dab1. Reelin-signaling components are enriched in axonal growth cones, where tyrosine phosphorylation of Dab1 is increased in response to Reelin. These findings suggest that Reelin-mediated phosphatidylinositol 3-kinase signaling in neuronal growth cones contributes to final neuron positioning in the mammalian brain by local modulation of protein kinase B and glycogen synthase kinase 3␤ kinase activities.Reelin is a large secreted protein of ϳ400 kDa that is defective in the ataxic reeler strain (1). In Reelin-deficient mice (2) and humans (3), neurons fail to migrate to their proper positions, resulting in abnormal lamination of the neocortex and the hippocampus. Reelin is also needed for the cortical positioning of Purkinje cells, a requirement for granule cell proliferation and foliation in the cerebellum.Reelin signaling requires binding to two members of the low density lipoprotein (LDL) 1 receptor gene family, the very low density lipoprotein receptor (VLDLR) and the apolipoprotein E receptor 2 (apoER2), on the surface of the migrating neurons (4, 5). The phenotype of knockout mice in which both of these Reelin receptors have been inactivated by gene targeting is indistinguishable from that of reeler mice, suggesting that both receptors are obligate components of the Reelin-signaling pathway (6).Further transmission of the signal is dependent upon the cytoplasmic adaptor protein Disabled-1 (Dab1). Dab1-deficient mice are indistinguishable from reeler and vldlr/apoer2 mutant mice (7-9). Dab1 interacts with NPXY motifs in the cytoplasmic domains of several LDL receptor family members (10), including VLDLR and apoER2 (6). Reelin binding to VLDLR and apoER2 induces tyrosine phosphorylation of Dab1 (5, 11). Replacement of tyrosine residues in Dab1 that are phosphorylated in response to Reelin by phenylalanines in knockin mice abolished Dab1 function (12). Furthermore, mice that lack both Reelin and Dab1 are no more affected than animals that lack only Reelin or Dab1 (11), suggesting that they are components of the same pathway.Tyrosine phosphorylation of Dab1 allows it to interact with nonreceptor tyrosine kinases including Abl and Src family members, suggesting that Dab1 itself might function as a regulator of tyrosine kinase signaling in the cell (13). The phosphotyrosine binding (PTB) domain of Dab1, which mediates the interaction of the adaptor protein with the NPXY motifs in the cytoplasmic domains of the...

The LDL receptor-related protein 1 (LRP1) is a multifunctional cell surface receptor that is highly expressed on neurons. Neuronal LRP1 in vitro can mediate ligand endocytosis, as well as modulate signal transduction processes. However, little is known about its role in the intact nervous system. Here, we report that mice that lack LRP1 selectively in differentiated neurons develop severe behavioral and motor abnormalities, including hyperactivity, tremor, and dystonia. Since their central nervous systems appear histoanatomically normal, we suggest that this phenotype is likely attributable to abnormal neurotransmission. This conclusion is supported by studies of primary cultured neurons that show that LRP1 is present in close proximity to the N-methyl-d-aspartate (NMDA) receptor in dendritic synapses and can be coprecipitated with NMDA receptor subunits and the postsynaptic density protein PSD-95 from neuronal cell lysates. Moreover, treatment with NMDA, but not dopamine, reduces the interaction of LRP1 with PSD-95, indicating that LRP1 participates in transmitter-dependent postsynaptic responses. Together, these findings suggest that LRP1, like other ApoE receptors, can modulate synaptic transmission in the brain