Scientists from Duke-NUS Medical School and the Mechanobiology Institute (MBI) at the National University of Singapore (NUS) have discovered a novel pathway to wake up dormant neural stem cells, offering potential new therapies for neurodevelopmental disorders such as autism, learning disabilities, and cerebral palsy.
In the mammalian adult brain, most neural stem cells, which originate from the nervous system and can grow into various types of brain cells, stay dormant until they receive specific signals that activate them. Once woken up, they produce new neurons, aiding in brain repair and growth.
Defects in neural stem cell activation are associated with ageing-related cognitive decline and neurodevelopmental disorders such as microcephaly, a condition where a baby's head is much smaller than expected because its brain has not developed properly. Neurodevelopmental disorders affect around five per cent of children and adolescents worldwide and lead to impaired cognition, communication, adaptive behaviour and psychomotor skills[1].
To study this activation, the scientists turned to Drosophila or fruit flies. Similar to mammals, the neural stem cells of fruit flies stay dormant till they are awakened. Their findings, published in Science Advances, showed that a type of glial cell named astrocytes—traditionally thought to provide structural and nutritional support—are important for waking up dormant neural stem cells in the brains of fruit flies.
Using super-resolution microscopy with 10-times magnifying power, the team of scientists examined the tiny fibre structures that are a hallmark of dormant neural stem cells of fruit flies. These fine structures, around 1.5 µm in diameter (or 20 times smaller than the diameter of a human hair), are protrusions extending from the cell body, and are rich in actin or protein filaments. A specific type of Formin protein can activate these filaments and cause them to assemble.
Dr Lin Kun Yang, who was a research fellow at Duke-NUS at the time of the study and the first author, said:
"We decided to home in on this pathway as variants in Formin levels are associated with neurodevelopmental disorders like microcephaly in humans. Understanding this pathway could provide new insights into developing solutions to treat neurodevelopmental disorders."
The scientists observed that astrocytes release a type of signalling protein called Folded gastrulation or Fog, which sparks a chain reaction that includes activating the Formin protein pathway to control the movement of actin filaments. Ultimately, these processes rouse neural stem cells from their dormant state. They then start to divide, creating new neurons that contribute to brain repair and development.
The receptor protein named GPCR in neural stem cells then responds to Fog secreted from astrocytes, activating the signalling pathway that controls the formation of actin filaments in neural stem cells. GPCRs have major roles in fundamental cell processes. As a result, the GPCR protein family has become a major drug target for treatments of various human diseases: 34 per cent of FDA-approved drugs target this family of proteins[2]. Therefore, understanding how this signalling pathway controls neural stem cell reactivation may provide a potential strategy for using existing drugs to treat neurodevelopmental disorders.
Professor Wang Hongyan, Acting Programme Director of Duke-NUS' Neuroscience & Behavioural Disorders Research Programme; and the senior author of the study, said:
"Our findings add new knowledge to the limited body of research on mechanisms governing the reactivation of dormant neural stem cells. With our discovery of astrocytes as a key player in the reactivation of neural stem cells, we now have a new way to influence neural stem cell behaviour."
Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, said:
"This not only advances our fundamental understanding of how astrocytes influence brain cell development but also opens new avenues for advancing therapies for neurological disorders, brain ageing and injury."
The scientists are currently investigating other signals from astrocytes that might influence the activity of neural stem cells. They also plan to explore whether similar mechanisms are involved in the development of the human brain.
Duke-NUS is a leader in medical research and education, with a commitment to improving patient care through innovative scientific discovery. This study is part of its ongoing efforts to deepen understanding of the fundamental mechanisms at play in the human brain to create new therapeutic approaches, especially for patients with neurological conditions.
This work was mainly supported by the National Research Foundation, Singapore under the National Medical Research Council (NMRC) Open Fund - Individual Research Grant (MOH-000143) and Open Fund - Young Individual Research Grant (MOH-001236) and administered by the Singapore Ministry of Health through the NMRC Office, MOH Holdings Pte Ltd, with additional support from several other grants.
[1] Dietrich, K. N. et al. Principles and practices of neurodevelopmental assessment in children: lessons learned from the Centers for Children's Environmental Health and Disease Prevention Research. Environ. Health Perspect. 113, 1437–1446 (2005).
[2] A. S. Hauser, M. M. Attwood, M. Rask-Andersen, H. B. Schioth, D. E. Gloriam, Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov 16, 829-842 (2017).
