Proteins stand up to nerve cell regression

Fruit fly studies reveal proteins that promote healthy nervous system development by preventing the reversal of nerve cell differentiation.

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.

SINGAPORE, 24 April 2019 – A study by Duke-NUS Medical School has 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.

Mutations in human Integrator genes intS1 and intS8 are 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. 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.”

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. Assoc
Prof Wang and her team previously showed that when dedifferentiation occurs, abnormal neural
stem cell-derived tumours can form in fruit fly brains. Nerve cell generation also becomes

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. 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. 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,” says Assoc Prof Wang.

Professor Patrick Casey, Senior Vice Dean of Research, Duke-NUS Medical School, commented,
“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.”

About Duke-NUS Medical School
Duke-NUS is a partnership between Duke University School of Medicine and the National
University of Singapore (NUS).

In 2005, with support from the Singapore government, NUS and Duke University, two academic
institutions with strong track records in research and education, committed to combine the unique
medical education curriculum at Duke University School of Medicine with the academic rigour
and rich resources offered by NUS, and to offer students an enriching and innovative medical
educational experience.

Duke-NUS is located on the main campus of the largest healthcare group in the country,
Singapore Health Services (SingHealth). This group collectively delivers multi-disciplinary care
among 42 clinical specialties across a large network of hospitals, national specialty centres and
polyclinics. Together, Duke-NUS and SingHealth constitute a leading, world class Academic
Medical Centre embodying the goal of delivering the highest levels of patient care, education and

For more information, please visit the website (link below)

For media enquiries, please contact:
Federico Graciano
Duke-NUS Medical School
Tel: +65 6601 3272
Email: [email protected]

Published: 24 Apr 2019

Contact details:

Duke-NUS Communications

Duke-NUS Medical School Singapore 8 College Road, Level 6 Singapore 169857

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Websites: Press release from Duke-NUS Medical School Research paper


Reference: Zhang Y, Koe CT, Tan YS, Ho J, Tan P, Yu F, Sung WK, and Wang H (2019). The Integrator Complex Prevents Intermediate Neural Progenitors Dedifferentiation back into Neural Stem Cells. Cell Reports Vol 27, Iss 4, pp 987–96. 23 Apr 2019. DOI: 10.1016/j.celrep.2019.03.089