Reciprocal Regulation of Very Low Density Lipoprotein Receptors (VLDLRs) in Neurons by Brain-derived Neurotrophic Factor (BDNF) and Reelin

Abstract

BDNF positively influences various aspects of neuronal migration, maturation, and survival in the developing brain. Reelin in turn mediates inhibitory signals to migrating neuroblasts, which is crucial for brain development. The interplay between BDNF and Reelin signaling in neurodevelopment is not fully understood. We show here that BDNF increased the levels of the Reelin receptor (VLDL receptor (VLDLR)) in hippocampal neurons by increasing gene expression. In contrast, Reelin decreased VLDLRs, which was accompanied by an increase in the levels of the E3 ligase Mylip/Idol in neurons. Down-regulation of Mylip/Idol using shRNAs abrogated the decrease in VLDLRs induced by Reelin. These results show that VLDLRs are tightly regulated in hippocampal neurons by both transcriptional and post-transcriptional mechanisms. The regulation of VLDLR by BDNF and Reelin may affect the migration of neurons and contribute to neurodevelopmental disorders in the nervous system.Background: VLDLR is a receptor for Reelin in brain neurons, but its mode of regulation is unclear.Results: BDNF increases VLDLR gene expression in hippocampal neurons, whereas Reelin decreases the receptor post-transcriptionally.Conclusion: Reelin down-regulates VLDLR via the E3 ubiquitin ligase Mylip/Idol.Significance: The dynamic regulation of VLDLR by BDNF and Reelin may be important for neuronal migration and brain development. BDNF positively influences various aspects of neuronal migration, maturation, and survival in the developing brain. Reelin in turn mediates inhibitory signals to migrating neuroblasts, which is crucial for brain development. The interplay between BDNF and Reelin signaling in neurodevelopment is not fully understood. We show here that BDNF increased the levels of the Reelin receptor (VLDL receptor (VLDLR)) in hippocampal neurons by increasing gene expression. In contrast, Reelin decreased VLDLRs, which was accompanied by an increase in the levels of the E3 ligase Mylip/Idol in neurons. Down-regulation of Mylip/Idol using shRNAs abrogated the decrease in VLDLRs induced by Reelin. These results show that VLDLRs are tightly regulated in hippocampal neurons by both transcriptional and post-transcriptional mechanisms. The regulation of VLDLR by BDNF and Reelin may affect the migration of neurons and contribute to neurodevelopmental disorders in the nervous system. Background: VLDLR is a receptor for Reelin in brain neurons, but its mode of regulation is unclear. Results: BDNF increases VLDLR gene expression in hippocampal neurons, whereas Reelin decreases the receptor post-transcriptionally. Conclusion: Reelin down-regulates VLDLR via the E3 ubiquitin ligase Mylip/Idol. Significance: The dynamic regulation of VLDLR by BDNF and Reelin may be important for neuronal migration and brain development.