Disease relevance of Lrp8

• Besides brain formation defects, apoER2-deficient mice also exhibit male infertility [1].
• Because insufficient expression of PHGPx is a major cause of infertility in men, these findings not only highlight an important new function for apoER2 that is unrelated to neuronal migration, but they also suggest a possible role for apoER2 in human infertility [1].

High impact information on Lrp8

• Apolipoprotein E receptor 2 (Apoer2), a member of the LDL receptor gene family, and its ligand Reelin control neuronal migration during brain development [2].
• Thus, alternative splicing of Apoer2, a novel component of the NMDA receptor complex, controls the modulation of NMDA receptor activity, synaptic neurotransmission, and memory by Reelin [2].
• Apoer2 is also essential for induction of long-term potentiation (LTP) in the adult brain [2].
• Here we show that Apoer2 is present in the postsynaptic densities of excitatory synapses where it forms a functional complex with NMDA receptors [2].
• Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation [3].

Biological context of Lrp8

• ApoER2/VLDLR double-knockout mice copy the reeler phenotype [4].
• This finding indicates that aggregation of apoER2 by multivalent ligands such as Reelin may be the structural basis for signal transduction [5].
• Apolipoprotein E receptor 2 (apoER2) is an important participant in the Reelin signaling pathway that directs cell positioning during embryogenesis [5].
• Reduced PHGPx expression in apoER2 knockout mice results in the inability of the sperm to regulate the cell volume and in abnormal sperm morphology and immotility [1].
• To study the role of granule cells for the lamina-specific ingrowth of afferents, the cyto- and fiberarchitecture of three mouse mutants (very low density lipoprotein receptor knockout mouse, apolipoprotein E receptor 2 knockout mouse, and reeler mouse) that show different degrees of granule cell migration defects were analyzed [6].

Anatomical context of Lrp8

• Specialized neurons throughout the developing central nervous system secrete Reelin, which binds to ApoE receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR), triggering a signal cascade that guides neurons to their correct position [7].
• Abnormal positioning of granule cells alters afferent fiber distribution in the mouse fascia dentata: morphologic evidence from reeler, apolipoprotein E receptor 2-, and very low density lipoprotein receptor knockout mice [6].
• Unlike layer formation, neuromuscular junction development requires a function of Reelin that is not mediated by Disabled1 or very-low-density lipoprotein receptors and apolipoprotein E receptor 2 receptors but by a distinct mechanism involving its protease activity [8].

Associations of Lrp8 with chemical compounds

• ApoE Receptor 2 Controls Neuronal Survival in the Adult Brain [9].

Physical interactions of Lrp8

• Moreover, phosphorylated but not native apoER2' co-precipitated with the Src family member Fgr [10].
• Binding experiments performed with Chinese hamster ovary cells expressing the human apoER2 showed that the receptor was able to bind VLDL containing either of the apoE isoforms, as well as the apoE-deficient VLDL [11].

Regulatory relationships of Lrp8

• Reelin, very-low-density lipoprotein receptor, and apolipoprotein E receptor 2 control somatic NMDA receptor composition during hippocampal maturation in vitro [12].
• Our results indicate that animals lacking apoER2 express higher levels of brain APP, as well as both key amyloid peptides, while apoE levels are slightly lower [13].

Other interactions of Lrp8

• RESULTS: We show that Reelin activates members of the Src family of non-receptor tyrosine kinases (SFKs) and that this activation is dependent on the Reelin receptors apoER2 and VLDLR and the adaptor protein Dab1 [14].
• Reelin is a secreted extracellular protein that binds to the very low density lipoprotein receptor and the apolipoprotein E receptor 2 on the surface of neurons [15].
• Finally, there was a complete absence of Reelin-induced tyrosine phosphorylation of Dab1 in cortical neurons from mice lacking both ApoER2 and VLDLR [16].
• Indeed, LDL was unable to induce p38MAPK activation in platelets of apoER2-deficient mice [10].
• Association of LDL to platelets resulted in tyrosine phosphorylation of apoER2', a process that was inhibited in the presence of PP1, an inhibitor of Src-like tyrosine kinases [10].
• 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 [17].

Analytical, diagnostic and therapeutic context of Lrp8

• Functional dissection of Reelin signaling by site-directed disruption of Disabled-1 adaptor binding to apolipoprotein E receptor 2: distinct roles in development and synaptic plasticity [18].
• Confocal microscopy revealed a high degree of co-localization of LDL and a splice variant of the LDL receptor family member apolipoprotein E receptor-2 (apoER2') at the platelet surface, suggesting that apoER2' may contribute to LDL-induced platelet signaling [10].

References