title: Nectin-like 4 Complexes with Choline Transporter-like Protein-1 and Regulates Schwann Cell Choline Homeostasis and Lipid Biogenesisin Vitro.
abstract: Nectin-like 4 (NECL4, CADM4) is a Schwann cell-specific cell adhesion molecule that promotes axo-glial interactions.In vitroandin vivostudies have shown that NECL4 is necessary for proper peripheral nerve myelination. However, the molecular mechanisms that are regulated by NECL4 and affect peripheral myelination currently remain unclear. We used anin vitroapproach to begin identifying some of the mechanisms that could explain NECL4 function. Using mass spectrometry and Western blotting techniques, we have identified choline transporter-like 1 (CTL1) as a putative complexing partner with NECL4. We show that intracellular choline levels are significantly elevated in NECL4-deficient Schwann cells. The analysis of extracellulard9-choline uptake revealed a deficit in the amount ofd9-choline found inside NECL4-deficient Schwann cells, suggestive of either reduced transport capabilities or increased metabolization of transported choline. An extensive lipidomic screen of choline derivatives showed that total phosphatidylcholine and phosphatidylinositol (but not diacylglycerol or sphingomyelin) are significantly elevated in NECL4-deficient Schwann cells, particularly specific subspecies of phosphatidylcholine carrying very long polyunsaturated fatty acid chains. Finally, CTL1-deficient Schwann cells are significantly impaired in their ability to myelinate neuritesin vitroTo our knowledge, this is the first demonstration of abona fidecell adhesion molecule, NECL4, regulating choline homeostasis and lipid biogenesis. Phosphatidylcholines are major myelin phospholipids, and several phosphorylated phosphatidylinositol species are known to regulate key aspects of peripheral myelination. Furthermore, the biophysical properties imparted to plasma membranes are regulated by fatty acid chain profiles. Therefore, it will be important to translate thesein vitroobservations toin vivostudies of NECL4 and CTL1-deficient mice.
authors.affiliation: From the Department of Biological Sciences, Rutgers, the State University of New Jersey, Newark, New Jersey 07102-1814 and.
authors.forename: Corey
authors.initials: C
authors.lastname: Heffernan
authors.affiliation: the Center for Advanced Proteomics Research, New Jersey Medical School, Newark, New Jersey 07103.
authors.forename: Mohit R
authors.initials: MR
authors.lastname: Jain
authors.affiliation: the Center for Advanced Proteomics Research, New Jersey Medical School, Newark, New Jersey 07103.
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.affiliation: From the Department of Biological Sciences, Rutgers, the State University of New Jersey, Newark, New Jersey 07102-1814 and.
authors.forename: Hyosung
authors.initials: H
authors.lastname: Kim
authors.affiliation: From the Department of Biological Sciences, Rutgers, the State University of New Jersey, Newark, New Jersey 07102-1814 and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Barretto
authors.affiliation: the Center for Advanced Proteomics Research, New Jersey Medical School, Newark, New Jersey 07103.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: From the Department of Biological Sciences, Rutgers, the State University of New Jersey, Newark, New Jersey 07102-1814 and maurep01@andromeda.rutgers.edu.
authors.forename: Patrice
authors.initials: P
authors.lastname: Maurel
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002794:Choline / Q000378:metabolism*; D006706:Homeostasis; D050155:Lipogenesis; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism; D010713:Phosphatidylcholines / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: C524956:Cadm4 protein, rat; D015816:Cell Adhesion Molecules, Neuronal; D026901:Membrane Transport Proteins; D010713:Phosphatidylcholines; D034741:RNA, Small Interfering; C065637:choline transporter; D002794:Choline
keywords: cell adhesion; choline; myelin; phosphatidylcholine; phosphatidylinositol