title: An endogenous vitamin K-dependent mechanism regulates cell proliferation in the brain subventricular stem cell niche.
abstract: Neural stem cells (NSC) persist in the adult mammalian brain, within the subventricular zone (SVZ). The endogenous mechanisms underpinning SVZ stem and progenitor cell proliferation are not fully elucidated. Vitamin K-dependent proteins (VKDPs) are mainly secreted factors that were initially discovered as major regulators of blood coagulation. Warfarin ((S(-)-3-acetonylbenzyl)-4-hydroxycoumarin)), a widespread anticoagulant, is a vitamin K antagonist that inhibits the production of functional VKDP. We demonstrate that the suppression of functional VKDPs production, in vitro, by exposure of SVZ cell cultures to warfarin or, in vivo, by its intracerebroventricular injection to mice, leads to a substantial increase in SVZ cell proliferation. We identify the anticoagulant factors, protein S and its structural homolog Gas6, as the two only VKDPs produced by SVZ cells and describe the expression and activation pattern of their Tyro3, Axl, and Mer tyrosine kinase receptors. Both in vitro and in vivo loss of function studies consisting in either Gas6 gene invalidation or in endogenous protein S neutralization, provided evidence for an important novel regulatory role of these two VKDPs in the SVZ neurogenic niche. Specifically, we show that while a loss of Gas6 leads to a reduction in the numbers of stem-like cells and in olfactory bulb neurogenesis, endogenous protein S inhibits SVZ cell proliferation. Our study opens up new perspectives for investigating further the role of vitamin K, VKDPs, and anticoagulants in NSC biology in health and disease.
authors.affiliation: Institut de Physiologie et Biologie Cellulaires, CNRS-UMR 6187 Université de Poitiers, Poitiers, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Gely-Pernot
authors.forename: Valérie
authors.initials: V
authors.lastname: Coronas
authors.forename: Thomas
authors.initials: T
authors.lastname: Harnois
authors.forename: Laetitia
authors.initials: L
authors.lastname: Prestoz
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mandairon
authors.forename: Anne
authors.initials: A
authors.lastname: Didier
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Berjeaud
authors.forename: Arnaud
authors.initials: A
authors.lastname: Monvoisin
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bourmeyster
authors.forename: Pablo García
authors.initials: PG
authors.lastname: De Frutos
authors.forename: Michel
authors.initials: M
authors.lastname: Philippe
authors.forename: Omar
authors.initials: O
authors.lastname: Benzakour
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019735:Carbon-Carbon Ligases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002552:Cerebral Ventricles / Q000166:cytology* / Q000201:enzymology; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D006899:Mixed Function Oxygenases / Q000378:metabolism; D017293:Protein S / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D055153:Stem Cell Niche / Q000187:drug effects; D014812:Vitamin K / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000494:pharmacology; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D019735:Carbon-Carbon Ligases; D036341:Intercellular Signaling Peptides and Proteins; D006899:Mixed Function Oxygenases; D017293:Protein S; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D014812:Vitamin K; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C513478:Tyro3 protein, mouse; C020660:glutamyl carboxylase