ASPM mutations disrupt human-specific neural stem cells, explaining microcephaly

Researchers at VIB and KU Leuven have shown how mutations in the ASPM gene interfere with a population of neural stem cells that is especially prominent in the developing human brain. The work, published in Developmental Cell, offers an explanation for why microcephaly, a condition marked by an abnormally small brain, affects people far more severely than mice carrying equivalent mutations.

A human-specific vulnerability

ASPM is the gene most often mutated in microcephaly. Children born with the condition have a markedly smaller brain and usually have cognitive impairment. Mouse models with the same genetic change, however, do not develop a notably smaller brain, which has long limited the use of rodents for studying the disorder.

Earlier studies found that ASPM mutations are present throughout the body of affected patients, yet their clear effects appear mainly in the developing brain. The new findings suggest that other cellular processes can compensate for the gene's loss in most tissues, but not in one particular type of brain cell.

Organoids reveal the affected cells

The team, led by Pierre Vanderhaeghen at the VIB-KU Leuven Center for Neuroscience, used human cortical organoids. These three-dimensional cultures reproduce certain features of the developing cerebral cortex. The organoids were grown from patient-derived cells and compared with matched controls, allowing the effects of the mutation to be examined in a human developmental setting.

The mutations affected outer radial glia, neural stem cells thought to underpin the expansion of the human brain. In the mutant organoids these cells were displaced too early and were not specified properly. The paper's title also points to disrupted orientation of the mitotic spindle, the structure that guides cell division, as part of the mechanism.

Dr Ridha Limame, co-first author of the study, described the organoids as a means of investigating the mutation in a human developmental context.

What the finding does and does not imply

Vanderhaeghen stressed that the gene has not gained a new role in humans. Instead, the cellular process it controls has become particularly important, and therefore particularly sensitive, during the expansion of the human brain. In this view, some genetic diseases hit the human brain harder because it develops differently from that of other species.

This framing matters for disease modelling. Conditions that look mild or absent in animal models may reflect differences in developmental biology, not an absence of gene function, and human-derived systems such as organoids may be needed to detect them.

Open questions

The source does not describe sample sizes or the number of patient lines used, and organoids capture only some aspects of fetal brain development. The authors also note that the precise functional contribution of outer radial glia, and how these cells behave during development, remains a challenge to resolve.

Next steps focus on the consequences for the mature brain. Vanderhaeghen highlighted several questions:

• Which types of neurons are most affected by the early defect?
• How do those neurons connect with others?
• Do the consequences go beyond a reduced number of neurons?

Answering these would help link a cellular defect in early development to the cognitive features seen in patients, and could clarify how other genetic brain disorders arise from human-specific developmental mechanisms.

Source: Why humans are more sensitive than other species to a brain developmental disease (Medical Xpress, 5 November 2026).

Image: AI-generated illustration.