Researchers at the Duke-NUS Medical School say they have found that members of the multiprotein Integrator complex, known for its role in gene regulation, are crucial for healthy brain development in fruit flies. The findings have implications for further understanding and treating neurodevelopmental disorders in humans, according to the scientists.
Mutations in human Integrator genes intS1 and intS8 were associated with neurodevelopmental syndrome, which is characterized by 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,” said Wang Hongyan, PhD, deputy director of the Duke-NUS Neuroscience and Behavioral Disorders Program and lead author of the study (“The Integrator Complex Prevents Dedifferentiation of Intermediate Neural Progenitors back into Neural Stem Cells”) in Cell Reports.
“Here, we demonstrate that the Drosophila Integrator complex prevents dedifferentiation of intermediate neural progenitors (INPs) during neural stem cell (neuroblast) lineage development. Loss of intS5, intS8, and intS1 generated ectopic type II neuroblasts. INP-specific knockdown of intS8, intS1, and intS2 resulted in the formation of excess type II neuroblasts, indicating that Integrator prevents INP dedifferentiation. Cell-type-specific DamID analysis identified 1413 IntS5-binding sites in INPs, including zinc-finger transcription factor earmuff (erm),” the investigators wrote.
“Furthermore, erm expression is lost in intS5 and intS8 mutant neuroblast lineages, and intS8 genetically interacts with erm to suppress the formation of ectopic neuroblasts. Taken together, our data demonstrate that the Drosophila Integrator complex plays a critical role in preventing INP dedifferentiation primarily by regulating a key transcription factor Erm that also suppresses INP dedifferentiation.”
Normally, neural stem cells in larval brains differentiate into intermediate neural progenitors, which ultimately form into nerve cells. Several factors are understood to prevent intermediate neural progenitor cells from turning back into neural stem cells, a process called dedifferentiation. Wang and her colleagues previously showed that when dedifferentiation occurs, abnormal neural stem cell-derived tumors can form in fruit fly brains. Nerve cell generation also becomes insufficient.
The Wang team mutated and turned off members of the Integrator complex in the fruit fly brains. Abnormal neural stem cells were formed when Integrator proteins were absent in brain cells. Turning off several Integrator genes in intermediate neural progenitor cells led to excessive formation of neural stem cells. Their investigations provided evidence that Integrator proteins help prevent intermediate neural progenitors from dedifferentiating into neural stem cells. A transcription factor called Earmuff, which is needed for the prevention of dedifferentiation, was identified as the primary target of Integrator complex proteins in the brain cells.
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, said Wang. They also show that Integrator complex proteins regulate Earmuff, which is a known dedifferentiation suppressor. “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,” continued Wang.
According to Patrick Casey, PhD, senior vice dean of research, Duke-NUS Medical School, “The study of the Integrator complex in neurodevelopment has been largely unexplored, and these findings provide valuable insights to better understand and treat neurodegenerative diseases in the future.”