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• W4251081011 abstract "We discovered a hypomorphic <i>reelin</i> (<i>Reln</i>) mutant with abnormal cortical lamination and no cerebellar hypoplasia. This mutant, <i>Reln^CTRdel</i>, carries a chemically induced splice-site mutation that truncates the C-terminal region (CTR) domain of RELN protein and displays remarkably distinct phenotypes from <i>reeler</i>. 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 <i>Vldlr^null</i> 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 <i>Reln^CTRdel</i>/<i>Apoer2^null</i> double homozygotes have phenotypes akin to those of <i>reeler</i> mutants, while <i>Reln^CTRdel</i>/<i>Vldlr^null</i> mice do not. Given that the receptor double knock-out mice resemble <i>reeler</i> mutants, we infer that <i>Reln^CTRdel</i>/<i>Apoer2^null</i> 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 <i>Reln^CTRdel</i> mice. A RELN-binding assay confirms that CTR truncation significantly decreases RELN binding to VLDLR, but not to APOER2. Together, the <i>in vitro</i> and <i>in vivo</i> results demonstrate that the CTR domain confers receptor-binding specificity of RELN. <b>SIGNIFICANCE STATEMENT</b> Reelin signaling is important for brain development and is associated with human type II lissencephaly. <i>Reln</i> mutations in mice and humans are usually associated with cerebellar hypoplasia. A new <i>Reln</i> mutant with a truncation of the C-terminal region (CTR) domain shows that <i>Reln</i> mutation can cause abnormal phenotypes in the cortex and hippocampus without cerebellar hypoplasia. Genetic analysis suggested that CTR truncation disrupts an interaction with the RELN receptor VLDLR (very low-density lipoprotein receptor); this was confirmed by a RELN-binding assay. This result provides a mechanistic explanation for the hypomorphic phenotype of the CTR-deletion mutant, and further suggests that <i>Reln</i> mutations may cause more subtle forms of human brain malformation than classic lissencephalies." @default.
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• W4251081011 date "2017-01-25" @default.
• W4251081011 modified "2023-10-17" @default.
• W4251081011 title "C-Terminal Region Truncation of RELN Disrupts an Interaction with VLDLR, Causing Abnormal Development of the Cerebral Cortex and Hippocampus" @default.
• W4251081011 doi "https://doi.org/10.1523/jneurosci.1826-16.2017" @default.
• W4251081011 hasPublicationYear "2017" @default.
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