Microcephaly-causative ASPM mutations disrupt mitotic spindle orientation and timely specification of human outer radial glia cells.

ASPM mutations in human cortical organoids cause premature mitotic spindle randomization in ventricular progenitors, followed by early delamination to the basal compartment.

• Why it matters: Primary microcephaly from ASPM is common, but how ASPM disruption produces species-specific outcomes in human development remains unclear.
• What they did: In human cortical organoids, the study tracked spindle orientation and delamination in ASPM-mutant progenitors, and tested whether spindle misorientation could mimic delamination via Inscuteable overexpression.
• The result: Delaminated progenitors resembled outer radial glia cells but failed to fully specify oRGC identity, with downregulation of key oRGC genes needed for amplification and maintenance.

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