{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T00:53:04Z","timestamp":1794012784008,"version":"4.8.0"},"reference-count":67,"publisher":"Society for Neuroscience","issue":"4","license":[{"start":{"date-parts":[[2017,7,25]],"date-time":"2017-07-25T00:00:00Z","timestamp":1500940800000},"content-version":"vor","delay-in-days":221,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2017,1,25]]},"abstract":"<jats:p>We discovered a hypomorphic<jats:italic>reelin<\/jats:italic>(<jats:italic>Reln<\/jats:italic>) mutant with abnormal cortical lamination and no cerebellar hypoplasia. This mutant,<jats:italic>Reln<jats:sup>CTRdel<\/jats:sup><\/jats:italic>, carries a chemically induced splice-site mutation that truncates the C-terminal region (CTR) domain of RELN protein and displays remarkably distinct phenotypes from<jats:italic>reeler<\/jats:italic>. 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<jats:italic>Vldlr<jats:sup>null<\/jats:sup><\/jats:italic>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<jats:italic>Reln<jats:sup>CTRdel<\/jats:sup><\/jats:italic>\/<jats:italic>Apoer2<jats:sup>null<\/jats:sup><\/jats:italic>double homozygotes have phenotypes akin to those of<jats:italic>reeler<\/jats:italic>mutants, while<jats:italic>Reln<jats:sup>CTRdel<\/jats:sup><\/jats:italic>\/<jats:italic>Vldlr<jats:sup>null<\/jats:sup><\/jats:italic>mice do not. Given that the receptor double knock-out mice resemble<jats:italic>reeler<\/jats:italic>mutants, we infer that<jats:italic>Reln<jats:sup>CTRdel<\/jats:sup><\/jats:italic>\/<jats:italic>Apoer2<jats:sup>null<\/jats:sup><\/jats:italic>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<jats:italic>Reln<jats:sup>CTRdel<\/jats:sup><\/jats:italic>mice. A RELN-binding assay confirms that CTR truncation significantly decreases RELN binding to VLDLR, but not to APOER2. Together, the<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>results demonstrate that the CTR domain confers receptor-binding specificity of RELN.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>Reelin signaling is important for brain development and is associated with human type II lissencephaly.<jats:italic>Reln<\/jats:italic>mutations in mice and humans are usually associated with cerebellar hypoplasia. A new<jats:italic>Reln<\/jats:italic>mutant with a truncation of the C-terminal region (CTR) domain shows that<jats:italic>Reln<\/jats:italic>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<jats:italic>Reln<\/jats:italic>mutations may cause more subtle forms of human brain malformation than classic lissencephalies.<\/jats:p>","DOI":"10.1523\/jneurosci.1826-16.2016","type":"journal-article","created":{"date-parts":[[2016,12,17]],"date-time":"2016-12-17T02:53:01Z","timestamp":1481943181000},"page":"960-971","source":"Crossref","is-referenced-by-count":25,"title":["C-Terminal Region Truncation of RELN Disrupts an Interaction with VLDLR, Causing Abnormal Development of the Cerebral Cortex and Hippocampus"],"prefix":"10.1523","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9498-4324","authenticated-orcid":false,"given":"Seungshin","family":"Ha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prem 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