Microcephaly is a congenital malformation that leads to a significantly reduced brain size and is often accompanied by developmental delay. An international research team led by Dr. Tran Tuoc from the Department of Human Genetics at Ruhr University Bochum, Germany, has discovered a previously unknown genetic cause for this condition.
Mutations in the EXOSC10 gene -- a central component of the RNA degradation complex ("exosome") -- cause primary microcephaly. The work is published in the journal Brain.
Precise balance of stem cells
During human brain development, neural stem cells must balance self-renewal and differentiation to build the cerebral cortex -- the brain's outer layer responsible for cognition and perception. If this balance is disturbed, malformations occur. "Recent advances in genome sequencing and genetic engineering are transforming our understanding of neurodevelopmental disorders," Dr. Tran Tuoc says.
He and his team identified de novo EXOSC10 mutations in patients with microcephaly through genomic screening of individuals with cortical malformations. To uncover how these mutations affect brain development, they generated conditional mouse models that reproduce the human mutations. In the developing mouse brain, partial loss of EXOSC10 led to premature differentiation of neural stem cells into neurons, reducing the pool of progenitors.
"This reduced the stem cell population, and the cerebral cortex remained smaller -- closely mirroring the patients' phenotype," says first author Dr. Pauline Ulmke.
Using RNA sequencing and RNA immunoprecipitation analyses, the researchers found that EXOSC10 normally degrades key transcripts of the Sonic hedgehog (Shh) signaling pathway, such as Scube1 and Scube3. When EXOSC10 function was reduced, these transcripts accumulated, leading to aberrantly high Shh activity.
"Notably, reducing Shh signaling in mutant mice largely rescued cortical size, pinpointing excessive Shh activity as the main driver of microcephaly in this context," concludes Dr. Ulmke.
Previously unknown connection
"Our study uncovers a previously unknown link between RNA decay and Sonic hedgehog signaling in brain development," explains Dr. Tran Tuoc. "It shows that a delicate balance of RNA degradation is essential to maintain proper growth of the cerebral cortex." Beyond identifying EXOSC10 as a novel microcephaly gene, the study provides mechanistic insight into how post-transcriptional RNA regulation controls progenitor dynamics and brain size.
The findings not only broaden the genetic landscape of primary microcephaly but also open new avenues for exploring RNA metabolism and signaling pathways in human brain malformations. This work highlights how state-of-the-art sequencing technologies and genetically engineered mouse models can reveal the molecular underpinnings of complex neurodevelopmental disorders.