Mutations in the ASPM gene are the most common cause of primary hereditary microcephaly in humans, a condition characterized by a severely reduced brain size. While ASPM has been studied in rodents and ferrets, these models only partially recapitulate the human condition due to significant differences in brain structure and complexity, particularly the lack of a folded cerebral cortex (gyrification). To better model human brain development, this study investigated the consequences of ASPM knockout in a non-human primate, the cynomolgus monkey.
The key findings are:
1. Severe Microcephaly: An ASPM KO monkey was generated using CRISPR/Cas9. This animal exhibited an extreme reduction in brain weight (over 70%) and cortical thickness, a phenotype far more severe than that observed in existing mouse or ferret models.
2. Selective Loss of Oligodendrocytes: A novel and major discovery was the significant and specific reduction in oligodendrocytes in the KO brain. This was accompanied by decreased levels of myelin proteins (MBP, MOG, Olig2), while astrocytes and microglia remained unaffected.
3. Impaired Neuronal Maturation and Synaptic Integrity: The cortical neurons in the KO monkey showed signs of immaturity, indicated by elevated Doublecortin (DCX) expression. Furthermore, there was a notable reduction in key synaptic proteins (PSD95, synaptophysin), linking the lack of myelination to synaptic deficits.
The authors propose that targeting multiple exons led to a complete loss of all ASPM protein isoforms, underlying the unprecedented severity of microcephaly and the unique oligodendrocyte deficit. This finding underscores the critical role of ASPM in gliogenesis and highlights the importance of oligodendrocytes in primate cortical expansion. Although limited to a single KO animal, this study provides compelling evidence for the value of non-human primate models in modeling human neurodevelopmental disorders.
Protein & Cell
Experimental study
Not applicable
Primate ASPM knockout causes severe microcephaly and oligodendrocyte loss in the brain
10-Oct-2025