LKB1 functions as a checkpoint for neuronal-glial balance during enteric nervous system development
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 lightsheet 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 S100b 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.
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BibTeX
@misc{lucas2026lkb1,
title = {{LKB1 functions as a checkpoint for neuronal-glial balance during enteric nervous system development}},
author = {Anthony Lucas and Florence Appaix and Jordan Allard and Marie Mével-Aliset and Anca Radu and Florence Fauvelle and Bertrand Favier and Alexei Grichine and Jochen Maurer and Pierre Hainaut and Laura Attardi and Marc Billaud and Sakina Torch and Chantal Thibert},
howpublished = {Genes and Development},
year = {2026},
month = nov,
doi = {10.1101/gad.353358.125},
url = {https://hal.science/hal-05852608v1},
note = {CC BY-NC-SA 4.0},
}
RIS
TY - UNPB
TI - LKB1 functions as a checkpoint for neuronal-glial balance during enteric nervous system development
AU - Anthony Lucas
AU - Florence Appaix
AU - Jordan Allard
AU - Marie Mével-Aliset
AU - Anca Radu
AU - Florence Fauvelle
AU - Bertrand Favier
AU - Alexei Grichine
AU - Jochen Maurer
AU - Pierre Hainaut
AU - Laura Attardi
AU - Marc Billaud
AU - Sakina Torch
AU - Chantal Thibert
PY - 2026
DA - 2026/11/09
PB - Genes and Development
DO - 10.1101/gad.353358.125
UR - https://hal.science/hal-05852608v1
AB - 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 lightsheet 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 S100b 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.
SN - 0890-9369
ER -