Autophagy controls neuronal differentiation by regulating the WNT-DVL signaling pathway

Area of Science:

• Neuroscience
• Cell Biology
• Developmental Biology

Background:

• Autophagy dysregulation is linked to neurological disorders, including Vici syndrome.
• Understanding autophagy's role in early brain development is critical for neurological disease research.

Purpose of the Study:

• To investigate the function of autophagy in human neuronal development.
• To model Vici syndrome using human embryonic stem cell-derived neurons with EPG5 mutations.

Main Methods:

• Generated neurons from human embryonic stem cells (hESCs).
• Created a Vici syndrome model by introducing EPG5 loss-of-function mutations.
• Utilized bafilomycin A1 to inhibit autolysosome formation in neuronal progenitor cells (NPCs).
• Analyzed WNT signaling pathway components and DVL2 degradation.

Main Results:

• Autophagy-related genes were upregulated in NPCs.
• Inhibition of autolysosome formation delayed neuronal differentiation.
• Autophagy negatively regulates WNT signaling via DVL2 degradation; its disruption delays differentiation.
• EPG5 mutations impaired autolysosome formation, affecting NPC differentiation and cortical development in organoids.
• Disrupted autophagy resulted in smaller organoids, mimicking Vici syndrome-associated microcephaly.

Conclusions:

• Autophagy is essential for timely neuronal differentiation and brain development.
• EPG5 mutations disrupt autophagy, leading to developmental defects and microcephaly relevant to Vici syndrome.
• Autophagy-mediated regulation of WNT signaling is a key mechanism in neuronal differentiation.