title: L1 syndrome mutations impair neuronal L1 function at different levels by divergent mechanisms.
abstract: Mutations in the human L1CAM gene cause neurodevelopmental disorders collectively referred to as L1 syndrome. Here, we investigated cellular pathomechanisms underlying two L1 syndrome mutations, R184Q and W1036L. We demonstrate that these mutations cause partial endoplasmic reticulum (ER) retention of L1, reduce L1 cell surface expression, but do not induce ER stress in neuronal NSC-34 cells. We provide evidence that surface trafficking of mutated L1 is affected by defective sorting to ER exit sites and attenuated ER export. However, in differentiated neuronal cultures and long-term cultured hippocampal slices, the L1-R184Q protein is restricted to cell bodies, whereas L1-W1036L also aberrantly localizes to dendrites. These trafficking defects preclude axonal targeting of L1, thereby affecting L1-mediated axon growth and arborization. Our results indicate that L1 syndrome mutations impair neuronal L1 function at different levels, firstly by attenuating ER export and secondly by interfering with polarized neuronal trafficking.
authors.affiliation: Institut für Anatomie und Zellbiologie, Universität Freiburg, 79104 Freiburg, Germany. michael.schaefer@zfn.uni-freiburg.de
authors.forename: Michael K E
authors.initials: MK
authors.lastname: Schäfer
authors.forename: Yun-Chung
authors.initials: YC
authors.lastname: Nam
authors.forename: Anice
authors.initials: A
authors.lastname: Moumen
authors.forename: Laura
authors.initials: L
authors.lastname: Keglowich
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bouché
authors.forename: Mercedes
authors.initials: M
authors.lastname: Küffner
authors.forename: Hans H
authors.initials: HH
authors.lastname: Bock
authors.forename: Fritz G
authors.initials: FG
authors.lastname: Rathjen
authors.forename: Cedric
authors.initials: C
authors.lastname: Raoul
authors.forename: Michael
authors.initials: M
authors.lastname: Frotscher
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016764:Cell Polarity / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D009154:Mutation / Q000235:genetics*; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics* / Q000502:physiology; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D009924:Organ Culture Techniques; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013577:Syndrome
chemical_list: D039842:Neural Cell Adhesion Molecule L1