Integrator complex, is a multi-protein, which are important for healthy brain development. A study by Duke-NUS Medical School has found the same. The multi-protein ‘Integrator complex’ 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 treating neuro-developmental disorders in humans.
Mutations in human Integrator genes intS1 and intS8; were associated with neuro-developmental 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. Associate Professor Wang Hongyan, Deputy Director of Duke-NUS’ Neuroscience and Behavioural Disorders Programme and lead author of the study, said, “We examined members of the Integrator complex in fruit fly brains to understand their roles in the development of the nervous system.”
Preventing intermediate neural progenitor cells
Normally, neural stem cells in larval brains differentiate into intermediate neural progenitors, which ultimately form into nerve cells. Several factors are understanding to preventing intermediate; neural progenitor cells from turning back; into neural stem cells, a process called de-differentiation. Assoc Prof Wang and her team previously showed that when de-differentiation occurs; abnormal neural stem cell-derived tumors can form in fruit fly brains. Nerve cell generation also becomes insufficient.
Assoc Prof Wang and her 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.
But their investigations provided evidence that Integrator proteins; but help prevent intermediate neural progenitors from de-differentiating into neural stem cells. However, a transcription factor called Earmuff, which is important for the prevention of de-differentiation; was identifying as the primary target of Integrator complex proteins in the brain cells.
Integrator complex proteins
The findings highlight the critical and novel roles played by Integrator complex proteins; in preventing de-differentiation, and thus in promoting brain development in fruit flies. They also show that Integrator complex proteins regulate Earmuff, which is a known de-differentiation suppressor. “Given that Integrator and Earmuff are highly conserving 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,” says Assoc Prof Wang.
Professor Patrick Casey, Senior Vice Dean of Research, Duke-NUS Medical School, commented; “The study of the Integrator complex in neuro-development has been largely unexplored; and these findings provide valuable insights to better understand and treat neuro-degenerative diseases in the future.”