LKB1 specifies neural crest cell fates through pyruvate-alanine cycling
| Autor: | Sakina Torch, Nadege Bondurand, Laurence Lafanechère, Karin Pernet-Gallay, Anca G. Radu, Lionel Larue, Nicolas Tricaud, Véronique Delmas, Renaud Blervaque, Chantal Thibert, Pierre Hainaut, Anthony Lucas, Marc Billaud, Nabeel Bardeesy, Florence Fauvelle, Veronique Pingault, Uwe Schlattner |
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| Přispěvatelé: | Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), IRMaGe (IRMaGe ), CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Physiopathologie du Cytosquelette, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Air Normand, Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Equipe n°3 Inserm U823, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Earth and Life Institute, Stress Agronomy Group, Université Catholique de Louvain = Catholic University of Louvain (UCL), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), INSERM U955, équipe 11, Service de Biochimie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de Recherche Biomédicale (IMRB), Massachusetts General Hospital Cancer Center, Harvard Medical School [Boston] (HMS), Ctr Rech, Institut Curie [Paris], Apoptose Cancer et Développement, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire, signalisation et cancer (GMSC), This work was founded by 'l’Institut National du Cancer' (Programme recherche translationnelle en cancérologie), 'la Ligue régionale contre le cancer' (comité de l’Isère R17030CC), 'l’Association pour la Recherche sur le Cancer' (Fondation ARC R17158CC), and NIH/NCI (1R01CA219670-01A1)., We are grateful to E. Fontaine and K. Padmanabhan for helpful comments about the results. We thank J. Courchet, B. Viollet, and J. Maurer for sharing cells and reagents. We thank S. Michallet, B. Sefrin, and P. Vernet from the animal facility of the Institute for Advanced Biosciences and F. Blanquet and C. Colomb from the animal facility PHTA of Grenoble. We are grateful to D. Bouvard for giving us the R26R mice and to G. Chevallier for help with mouse breeding and genotyping. We thank V. Blanc-Marquis for technical help. S. Michallet and M. Schweitzer were very helpful with excellent technical assistance. C. Caron helped us with human sample studies. This work benefited from the help of T. Dufourd and M. Aguilera during their internships in the laboratory. J. Delaroche and A. Bertrand from the electron microscopy facility of the Neuroscience Institute of Grenoble performed semithin sections, staining, and electronic microscopy experiments and analyses. We thank N. Gadot and the ANIPATH facility, University Lyon1 Laennec, for tissue sections., Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences de Montpellier (INM), Hamant, Sarah, Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
[SDV]Life Sciences [q-bio]
[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] AMP-Activated Protein Kinases Enteric Nervous System Mice 0302 clinical medicine [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] Pyruvic Acid skin and connective tissue diseases ComputingMilieux_MISCELLANEOUS Research Articles Mice Knockout 0303 health sciences education.field_of_study Multidisciplinary Alanine Neural crest Peripheral Nervous System Diseases SciAdv r-articles Cell Differentiation Cell biology Mitochondria [SDV] Life Sciences [q-bio] medicine.anatomical_structure Phenotype Neural Crest embryonic structures Melanocytes Stem cell Signal transduction Neuroglia Signal Transduction Research Article congenital hereditary and neonatal diseases and abnormalities Population Schwann cell [SDV.CAN]Life Sciences [q-bio]/Cancer Cell fate determination Biology Protein Serine-Threonine Kinases 03 medical and health sciences medicine Animals Gene Silencing education 030304 developmental biology [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis Cell Biology Embryonic stem cell [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis Nerve Degeneration Enteric nervous system Energy Metabolism 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Science Advances Science Advances, American Association for the Advancement of Science (AAAS), 2019, 5 (7), pp.eaau5106. ⟨10.1126/sciadv.aau5106⟩ Science Advances, 2019, 5 (7), pp.eaau5106. ⟨10.1126/sciadv.aau5106⟩ |
| ISSN: | 2375-2548 |
| DOI: | 10.1126/sciadv.aau5106⟩ |
| Popis: | Glial specification of neural crest cells requires the tumor suppressor LKB1-mediated action on alanine biosynthesis. Metabolic processes underlying the development of the neural crest, an embryonic population of multipotent migratory cells, are poorly understood. Here, we report that conditional ablation of the Lkb1 tumor suppressor kinase in mouse neural crest stem cells led to intestinal pseudo-obstruction and hind limb paralysis. This phenotype originated from a postnatal degeneration of the enteric nervous ganglia and from a defective differentiation of Schwann cells. Metabolomic profiling revealed that pyruvate-alanine conversion is enhanced in the absence of Lkb1. Mechanistically, inhibition of alanine transaminases restored glial differentiation in an mTOR-dependent manner, while increased alanine level directly inhibited the glial commitment of neural crest cells. Treatment with the metabolic modulator AICAR suppressed mTOR signaling and prevented Schwann cell and enteric defects of Lkb1 mutant mice. These data uncover a link between pyruvate-alanine cycling and the specification of glial cell fate with potential implications in the understanding of the molecular pathogenesis of neural crest diseases. |
| Databáze: | OpenAIRE |
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