LKB1 specifies neural crest cell fates through pyruvate-alanine cycling

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

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / metabolism*
  • Animals
  • Cell Differentiation / genetics
  • Energy Metabolism
  • Enteric Nervous System
  • Gene Silencing
  • Melanocytes / metabolism
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Nerve Degeneration / etiology
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Neural Crest / cytology*
  • Neural Crest / metabolism*
  • Neuroglia / cytology
  • Neuroglia / metabolism
  • Peripheral Nervous System Diseases / etiology
  • Peripheral Nervous System Diseases / metabolism
  • Peripheral Nervous System Diseases / pathology
  • Phenotype
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyruvic Acid / metabolism*
  • Signal Transduction

Substances

  • Pyruvic Acid
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Alanine