A study published yesterday in Cell Reports shows that members of the multiprotein ‘Integrator complex,’ which is known for its role in gene regulation, are crucial for healthy brain development in fruit flies. The findings have implications for further understanding and treatment of neurodevelopmental disorders in humans.
Mutations in human Integrator genes intS1 and intS8 were associated with neurodevelopmental syndrome, which is characterized by profound intellectual disability, epilepsy, and subtle structural brain abnormalities. However, the role of the Integrator complex during brain development has not been well understood.
“We examined members of the Integrator complex in fruit fly brains to understand their roles in the development of the nervous system,” says senior author Wang Hongyan of Duke-NUS.
Normally, neural stem cells in larval brains differentiate into intermediate neural progenitors, which ultimately develop into nerve cells. But sometimes, these intermediate neural progenitors ‘dedifferentiate’ back into neural stem cells. Wang and her team previously showed that when dedifferentiation occurs, abnormal neural stem cell–derived tumors can form in fruit fly brains, and nerve cell generation becomes insufficient.
To learn the role of the Integrator complex in neural development, the team mutated and turned off members of the Integrator complex in fly brains. The researchers’ findings provided evidence that Integrator proteins help prevent intermediate neural progenitors from dedifferentiating into neural stem cells. Additionally, the team identified a transcription factor called Earmuff—which is needed for the prevention of dedifferentiation—as the primary target of Integrator complex proteins in the neurons.
The findings highlight the critical and novel roles played by Integrator complex proteins in preventing dedifferentiation, and thus in promoting brain development in fruit flies. They also show that Integrator complex proteins regulate Earmuff.
“Given that Integrator and Earmuff are highly conserved in flies and humans, our study will facilitate understanding the function of their mammalian and human counterparts during brain development, in addition to understanding potential disease mechanisms,” Wang says.
Image: Ectopic neural stem cells are formed upon loss of the Integrator S5 gene in the brain. Single neural stem cell lineages are marked by CD8-GFP and white dotted lines. Type II neural stem cells, indicated by arrows, are positive for Deadpan (Dpn) and negative for Asense (Ase). Scale bar, 10μm. Image courtesy of Yingjie Zhang and Chwee Tat Koe.