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

Area of Science:

• Developmental biology
• Neuroscience
• Metabolism

Background:

• The energy status of enteric progenitors is key to enteric nervous system (ENS) formation, but poorly understood.
• Previous work identified LKB1's role in postnatal ENS maintenance via amino acid homeostasis.

Purpose of the Study:

• To investigate the function of LKB1 during embryonic ENS development.
• To understand how LKB1 regulates neurogliogenesis and ENS formation.

Main Methods:

• Conditional Lkb1 inactivation in mouse neural crest progenitors.
• Advanced 3D imaging: light sheet and adaptive optics confocal microscopy.
• Analysis of glial stress markers, oxidative stress, DNA damage, and p53 activation.

Main Results:

• Lkb1 loss impaired neuronal differentiation and caused glial degeneration, resulting in hypoganglionosis.
• Elevated oxidative stress, DNA damage, and p53 activation were observed in Lkb1-deficient progenitors and derivatives.
• p53 ablation partially rescued glial maintenance but not ENS architecture or neuron numbers.

Conclusions:

• LKB1 acts as a critical metabolic checkpoint controlling neuronal-glial balance during ENS development.
• Dysregulated LKB1 signaling may contribute to human enteric neurogliopathies.