LKB1 functions as a checkpoint for neuronal–glial balance during enteric nervous system development

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Abstract
How the energy status of enteric progenitors controls neurogliogenesis and the subsequent formation of the complex enteric nervous system (ENS) remains poorly understood. We previously showed that the tumor suppressor kinase LKB1 is essential for postnatal ENS maintenance through amino acid homeostasis. Here, we investigated LKB1's functions during embryonic ENS formation using a genetically engineered mouse model with conditional Lkb1 inactivation in neural crest progenitors during gut colonization. Using advanced 3D imaging techniques on cleared tissue including light sheet microscopy and adaptive optics confocal microscopy, we found that Lkb1 loss impairs early neuronal differentiation followed by progressive glial degeneration, leading to hypoganglionosis and compromised digestive tissue integrity. Notably, Lkb1 inactivation induced a transient upregulation of the glial stress marker S100β during gestation, suggestive of a reactive glial state preceding glial loss. Consistent with this response, Lkb1 loss elevated oxidative stress in the digestive tract and in neural crest progenitors and their glial derivatives, triggering DNA damage and p53 activation. Although p53 ablation rescued glial specification in vitro and glial maintenance in vivo, it only partially restored ENS architecture in vivo without rescuing enteric neuron numbers. Together, these findings establish LKB1 as a critical metabolic checkpoint governing neuronal–glial balance during ENS development and suggest that dysregulated LKB1 signaling may contribute to human enteric neurogliopathies.
Funding Information
  • Ligue Contre le Cancer
  • Fondation Association pour la Recherche sur le Cancer
  • Agence Nationale de la Recherche (ANR-15-IDEX-02)
  • Centre National de la Recherche Scientifique
  • Institut National de la Santé et de la Recherche Médicale
  • University Grenoble Alpes
  • Agence Nationale de la Recherche (ANR-17-EURE-0003)
  • Ligue Contre le Cancer

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