Scientists have identified a new pathway that can activate dormant neural stem cells, paving the way for innovative treatments for neurodevelopmental disorders like autism, learning disabilities, and cerebral palsy.
Researchers at Duke-NUS Medical School and the Mechanobiology Institute (MBI) at the National University of Singapore have discovered a new method to stimulate inactive neural stem cells, which may lead to promising therapies for neurodevelopmental conditions such as autism, learning challenges, and cerebral palsy.
In the adult mammalian brain, most neural stem cells, which originate from the nervous system and can develop into various brain cell types, remain inactive until they receive particular signals that prompt their activation. Once activated, these cells create new neurons, promoting brain healing and development.
Issues with the activation of neural stem cells are linked to cognitive decline due to aging and neurodevelopmental disorders like microcephaly, a condition where a baby’s head is significantly smaller than normal because of improper brain development. Neurodevelopmental disorders impact about 5% of children and teenagers globally, resulting in challenges with cognitive functions, communication, adaptive behavior, and motor skills.
To investigate this activation process, the researchers studied Drosophila, commonly known as fruit flies. Much like mammals, the neural stem cells in fruit flies remain inactive until they are stimulated. Their research, published in Science Advances, revealed that a type of glial cell called astrocytes—previously believed to solely provide structural and nutritional support—plays a crucial role in activating dormant neural stem cells in the brains of fruit flies.
The researchers deployed super-resolution microscopy with a magnification 10 times greater than usual to analyze the small fiber structures characteristic of inactive neural stem cells. These structures, which measure around 1.5 µm in diameter (20 times thinner than a human hair), are extensions from the cell body that contain a high concentration of actin or protein filaments. A specific variant of Formin protein can trigger the activation and assembly of these filaments.
Dr. Lin Kun Yang, a research fellow at Duke-NUS during the study and the lead author, commented:
“We focused on this pathway because variations in Formin levels are linked to neurodevelopmental issues such as microcephaly in humans. Understanding this pathway could lead to new treatment options for neurodevelopmental disorders.”
The scientists determined that astrocytes release a signaling protein called Folded gastrulation (Fog), which initiates a sequence of events, including activating the Formin protein pathway that regulates actin filament movement. As a result, these processes awaken dormant neural stem cells, prompting them to divide and produce new neurons that aid in brain repair and growth.
The receptor protein GPCR in neural stem cells responds to the Fog released by astrocytes, triggering a signaling pathway that influences the formation of actin filaments in these cells. GPCRs play essential roles in various cellular functions, making this protein family a key target for drugs treating a range of human diseases: 34% of FDA-approved medications target GPCRs. Consequently, understanding this signaling pathway’s role in neural stem cell activation may provide a viable strategy for utilizing existing drugs to manage neurodevelopmental disorders.
Professor Wang Hongyan, Acting Programme Director of the Neuroscience & Behavioural Disorders Research Programme at Duke-NUS and senior author of the study, stated:
“Our research enriches the limited knowledge surrounding the mechanisms that activate dormant neural stem cells. With our discovery that astrocytes are crucial for this process, we now have a new method to regulate the behavior of these stem cells.”
Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, remarked:
“This not only enhances our understanding of the role astrocytes play in brain cell development but also paves the way for advancing therapies targeting neurological disorders, brain aging, and injury.”
The researchers are also exploring other signals from astrocytes that may affect neural stem cell activity, and they plan to examine whether similar mechanisms exist in human brain development.
Duke-NUS is a forefront institution in medical research and education, dedicated to enhancing patient care through innovative scientific discoveries. This study is part of ongoing efforts to improve understanding of the essential mechanisms in the human brain to develop new therapeutic approaches, especially for those suffering from neurological disorders.
This research was primarily funded by the National Research Foundation of Singapore under the National Medical Research Council (NMRC) Open Fund — Individual Research Grant (MOH-000143) and the Open Fund — Young Individual Research Grant (MOH-001236), administered by the Singapore Ministry of Health through the NMRC Office, MOH Holdings Pte Ltd, alongside support from several other grants.
Notes:
[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).
