title: Lysophosphatidylcholine Drives Neuroblast Cell Fate.
abstract: Neuronal differentiation plays a key role during embryogenesis. However, based on the capacity of neuronal stem cells to either generate or regenerate neurons and because differentiation stops aberrant neuroblasts proliferation, neuronal differentiation is crucial during neuropathological conditions. Although phosphatidylcholine (PtdCho) has been proposed as an important molecule for neurite growth and neuronal regeneration, the identity of the molecular target has remained elusive. This study originally describes that lysophosphatidylcholine (LPtdCho), either exogenously supplied or generated by the imbalance of PtdCho metabolism through the enzymatic action of cytosolic phospholipase A2, acts as a neurotrophic-like factor. We demonstrated that LPtdCho induces neuronal differentiation by activation of the small G protein Ras followed by the Raf/MEK/ERK signaling pathway. Accordingly, LPtdCho redirects neuroblasts gene expression leading to the generation of functional mature neurons expressing βIII-tubulin and having increased acetylcholinesterase activity and membrane biosynthesis required for neuritogenesis. These findings provide mechanistic details of the role of cytidine-5-diphosphocholine (CDP-choline) and PtdCho as neuroprotectors. Furthermore, as LPtdCho recapitulates the effect of the therapeutic agent retinoic acid, these results open new avenues for drug discovery for the treatment of neuropathological conditions.
authors.affiliation: Instituto de Biología Molecular y Celular de Rosario (IBR- CONICET) Ocampo y Esmeralda, Predio CONICET and Departamento de Ciencias Biológicas, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, 2000, Argentina.
authors.forename: Luciana
authors.initials: L
authors.lastname: Paoletti
authors.affiliation: Instituto de Biología Molecular y Celular de Rosario (IBR- CONICET) Ocampo y Esmeralda, Predio CONICET and Departamento de Ciencias Biológicas, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, 2000, Argentina.
authors.forename: Pablo
authors.initials: P
authors.lastname: Domizi
authors.affiliation: Instituto de Biología Molecular y Celular de Rosario (IBR- CONICET) Ocampo y Esmeralda, Predio CONICET and Departamento de Ciencias Biológicas, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, 2000, Argentina.
authors.forename: Hebe
authors.initials: H
authors.lastname: Marcucci
authors.affiliation: Instituto de Biología Molecular y Celular de Rosario (IBR- CONICET) Ocampo y Esmeralda, Predio CONICET and Departamento de Ciencias Biológicas, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, 2000, Argentina.
authors.forename: Aneley
authors.initials: A
authors.lastname: Montaner
authors.affiliation: Instituto de Biología Molecular y Celular de Rosario (IBR- CONICET) Ocampo y Esmeralda, Predio CONICET and Departamento de Ciencias Biológicas, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, 2000, Argentina.
authors.forename: Dario
authors.initials: D
authors.lastname: Krapf
authors.affiliation: INIBIBB-UNS-CONICET, Camino La Carrindanga KM 7, Bahía Blanca, 8000, Argentina.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Salvador
authors.affiliation: Instituto de Biología Molecular y Celular de Rosario (IBR- CONICET) Ocampo y Esmeralda, Predio CONICET and Departamento de Ciencias Biológicas, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, 2000, Argentina. banchio@ibr-conicet.gov.ar.
authors.forename: Claudia
authors.initials: C
authors.lastname: Banchio
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000187:drug effects; D006801:Humans; D008244:Lysophosphatidylcholines / Q000378:metabolism / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000378:metabolism; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism; D015290:Second Messenger Systems; D014212:Tretinoin / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D008244:Lysophosphatidylcholines; D010713:Phosphatidylcholines; D014212:Tretinoin; D054510:Phospholipases A2, Cytosolic; D018631:ras Proteins; D002118:Calcium
keywords: Cell differentiation; MAPKK; Neuron; Neurotrophic factor; Phosphatidylcholine; Retinoic acid