Modeling microcephaly with cerebral organoids reveals a WDR62-CEP170-KIF2A pathway promoting cilium disassembly in...

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Primary microcephaly is a neurological disorder characterized by an abnormally small brain.
• Mutations in centrosomal proteins, such as WDR62 and KIF2A, are known causes of primary microcephaly.
• The precise molecular mechanisms underlying human microcephaly remain largely unknown.

Purpose of the Study:

• To elucidate the role of WDR62 in microcephaly pathogenesis.
• To investigate the molecular pathway involving WDR62, CEP170, and KIF2A in neural progenitor cell regulation.
• To establish and utilize mouse models and human cerebral organoids for studying microcephaly.

Main Methods:

• Generation of WDR62-deficient mice and human cerebral organoids.
• Analysis of neural progenitor cell (NPC) behavior, including proliferation and differentiation.
• Investigation of primary cilium structure and dynamics, focusing on disassembly.
• Assessment of protein interactions and localization, particularly WDR62, CEP170, and KIF2A at the basal body.
• Rescue experiments involving enhanced KIF2A expression.

Main Results:

• WDR62 deletion in mice and organoids led to reduced brain size due to disrupted neural progenitor cells (NPCs), including outer radial glia (oRG).
• WDR62 ablation caused impaired cilium disassembly, resulting in longer cilia and delayed cell cycle progression, decreased NPC proliferation, and premature differentiation.
• WDR62 facilitates CEP170 localization to the primary cilium's basal body, which in turn recruits KIF2A for cilium disassembly.
• Reduced WDR62 diminished KIF2A's basal body localization; however, increased KIF2A expression partially restored normal cilium length and NPC proliferation.

Conclusions:

• A novel WDR62-CEP170-KIF2A pathway regulating primary cilium disassembly has been identified.
• Disruption of this pathway contributes to microcephaly by affecting neural progenitor cell proliferation and differentiation.
• Cerebral organoid and mouse models are valuable tools for dissecting the mechanisms of microcephaly.