C-Terminal Region Truncation of RELN Disrupts an Interaction with VLDLR, Causing Abnormal Development of the Cerebral Cortex and Hippocampus

• Published in: The Journal of neuroscience 2017-01, Vol.37 (4), p.960-971
• Main Authors: Ha, Seungshin, Tripathi, Prem P, Mihalas, Anca B, Hevner, Robert F, Beier, David R
• Format: Article
• Language: English
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1826-16.2017

We discovered a hypomorphic reelin(Reln) mutant with abnormal cortical lamination and no cerebellar hypoplasia. This mutant, RelnCTRdel, carries a chemically induced splice-site mutation that truncates the C-terminal region (CTR) domain of RELN protein and displays remarkably distinct phenotypes from reeler. The mutant does not have an inverted cortex, but cortical neurons overmigrate and invade the marginal zone, which are characteristics similar to a phenotype seen in the cerebral cortex of Vldlrnull mice. The dentate gyrus shows a novel phenotype: the infrapyramidal blade is absent, while the suprapyramidal blade is present and laminated. Genetic epistasis analysis showed that RelnCTRdel/Apoer2null double homozygotes have phenotypes akin to those of reeler mutants, while RelnCTRdel/Vldlrnull mice do not. Given that the receptor double knock-out mice resemble reeler mutants, we infer that RelnCTRdel/Apoer2null double homozygotes have both receptor pathways disrupted. This suggests that CTR-truncation disrupts an interaction with VLDLR (very low-density lipoprotein receptor), while the APOER2 signaling pathway remains active, which accounts for the hypomorphic phenotype in RelnCTRdel mice. A RELN-binding assay confirms that CTR truncation significantly decreases RELN binding to VLDLR, but not to APOER2. Together, the in vitro and in vivo results demonstrate that the CTR domain confers receptor-binding specificity of RELN.