Developmental Cell· 2026Q1
Microcephaly-causative ASPM mutations disrupt mitotic spindle orientation and timely specification of human outer radial glia cells
- 2citations
- Q1SCImago
- 2026year
Short summary
ASPM mutations, linked to primary microcephaly, cause human cortical progenitors to delaminate prematurely and adopt outer radial glia (oRGC) characteristics, disrupting the timely generation of this key cell population.
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Key points
- ASPM mutations cause transient mitotic spindle randomization in human cortical progenitors.
- Mutant progenitors delaminate basally and precociously become outer radial glia (oRGC) cells.
- This process disrupts the timely generation of oRGCs, a progenitor population expanded in human corticogenesis.
- ASPM regulates oRGC generation by controlling mitotic spindle orientation.
AI-generated from the title and abstract; the full text is not read.
Abstract
Summary Abnormal spindle-like, microcephaly-associated ( ASPM ) is the most commonly mutated gene in primary microcephaly (MCPH), characterized by reduced brain size and intellectual deficiency. The mechanisms underlying MCPH have remained unclear, as ASPM disruption leads to distinct phenotypes depending on the species studied. Here, we studied the impact of ASPM pathogenic mutations on human corticogenesis in organoid models. We found that at earliest stages of neurogenesis, ASPM mutant cortical progenitors, located at the apical surface of the neuroepithelium, display transient mitotic spindle randomization. The mutant progenitors then delaminate basally to adopt precociously the characteristics of outer radial glia cells (oRGC), a population of progenitors selectively amplified in human corticogenesis. Subsequently, cortical progenitors are depleted through decreased amplification and increased apoptosis. Thus, ASPM regulates the timely generation of oRGC by controlling mitotic spindle orientation, shedding light on how species-specific features of neurogenesis may confer vulnerability to neurodevelopmental diseases.
The authors' abstract, as published at the source. Developmental Cell, 2026 · DOI ↗
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Field: Developmental Neuroscience
Developmental NeuroscienceNeuroscience