title: A neuronal VLDLR variant lacking the third complement-type repeat exhibits high capacity binding of apoE containing lipoproteins.
abstract: Very-low-density lipoprotein receptor (VLDLR) is a multi ligand apolipoprotein E (apoE) receptor and is involved in brain development through Reelin signaling. Different forms of VLDLR can be generated by alternative splicing. VLDLR-I contains all exons. VLDLR-II lacks an O-linked sugar domain encoded by exon 16, while VLDLR-III lacks the third complement-type repeat in the ligand binding domain encoded by exon 4. We quantitatively compared lipoprotein binding to human VLDLR variants and analyzed their mRNA expression in both human cerebellum and mouse brain. VLDLR-III exhibited the highest capacity in binding to apoE enriched beta-VLDL in vitro and was more effective in removing apoE containing lipoproteins from the circulation than other variants in vivo. In human cerebellum, the major species was VLDLR-II, while the second most abundant species was a newly identified VLDLR-IV which lacks both exon 4 and 16. VLDLR-I was present at low levels. In adult mice, exon 4 skipping varied between 30 and 47% in different brain regions, while exon 16 skipping ranged by 51-76%. Significantly higher levels of VLDLR proteins were found in mouse cerebellum and cerebral cortex than other regions. The deletions of exon 4 and exon 16 frequently occurred in primary neurons, indicating that newly identified variant VLDLR-IV is abundant in neurons. In contrast, VLDLR mRNA lacking exon 4 was not detectable in primary astrocytes. Such cell type-specific splicing patterns were found in both mouse cerebellum and cerebral cortex. These results suggest that a VLDLR variant lacking the third complement-type repeat is generated by neuron-specific alternative splicing. Such differential splicing may result in different lipid uptake in neurons and astrocytes.
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Keiko
authors.initials: K
authors.lastname: Sakai
authors.forename: Oliver
authors.initials: O
authors.lastname: Tiebel
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: Ljungberg
authors.forename: Merry
authors.initials: M
authors.lastname: Sullivan
authors.forename: Hye-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Tomoya
authors.initials: T
authors.lastname: Terashima
authors.forename: Rongying
authors.initials: R
authors.lastname: Li
authors.forename: Kunihisa
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Lu
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Oka
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D053419:Lipoproteins, IDL / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism*; D000091042:Reelin Protein
chemical_list: D001057:Apolipoproteins E; D053419:Lipoproteins, IDL; D012333:RNA, Messenger; D011973:Receptors, LDL; D000091042:Reelin Protein; C036053:VLDL receptor; D002784:Cholesterol; C000717127:RELN protein, human; C000717128:Reln protein, mouse