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Sci Adv. 2019 Jul 17;5(7):eaau5106. doi: 10.1126/sciadv.aau5106. eCollection 2019 Jul.

LKB1 specifies neural crest cell fates through pyruvate-alanine cycling.

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Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France.
Univ. Grenoble Alpes, INSERM, U1216, Grenoble Institute of Neurosciences GIN, 38000 Grenoble, France.
Univ. Grenoble Alpes, INSERM, US17, MRI facility IRMaGe, 38000 Grenoble, France.
Institut Curie, Normal and Pathological Development of Melanocytes, CNRS UMR3347; INSERM U1021; Equipe Labellisée-Ligue Nationale Contre le Cancer, Orsay, France.
Laboratory of Fundamental and Applied Bioenergetics, Univ Grenoble Alpes, 38185 Grenoble, France.
INSERM U1055, 38041 Grenoble France.
INSERM U1051, Institut des Neurosciences de Montpellier (INM), Université de Montpellier, Montpellier, France.
INSERM U1163, Institut Imagine, Paris, France.
Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
"Clinical and experimental model of lymphomagenesis" Univ Lyon, Université Claude Bernard Lyon1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon France.


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.

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