Researchers at the National University of Singapore’s Yong Loo Lin School of Medicine (NUS Medicine) say they have identified a key protein that can help regenerate neural stem cells, which may improve age-related declines in the brain’s production of new neurons. The protein is a transcription factor called cyclin D-binding myb-like transcription factor 1 (DMTF1), and the work was published in Science Advances.
The team reports that DMTF1 acts as a critical driver of neural stem cell function during the aging process, and that restoring DMTF1 levels in “aged” neural stem cells was enough to bring back their ability to regenerate in laboratory experiments. Neural stem cells are responsible for generating new neurons that support learning and memory, and they tend to lose their ability to renew with age.
What the study found
In the study, DMTF1 was found to be down-regulated in neural stem cells in a premature aging model driven by telomerase deficiency, which is linked to telomere attrition. The researchers report that increasing (up-regulating) DMTF1 rescued the impaired proliferation of telomere-dysfunctional neural stem cells.
NUS Medicine and a related release describe DMTF1 as a transcription factor, meaning it regulates genes so they are expressed correctly in the intended cells. The group also says DMTF1 levels are repressed in “aged” neural stem cells and that restoring expression is sufficient to restore regeneration capabilities.
ScienceDaily similarly reports that boosting DMTF1 restored neural stem cells’ ability to regenerate “even when age-related damage has set in,” and notes that without it these cells struggle to renew and support memory and learning. The ScienceDaily report adds that the findings raise hopes for treatments that could slow or even reverse aspects of brain aging.
How DMTF1 may work
According to the Science Advances abstract, DMTF1 promotes neural stem cell proliferation by regulating the transcription of Arid2 and Ss18, described as two subunits of SWI/SNF complexes. Those SWI/SNF complexes are reported to mediate H3K27ac at E2F gene promoters, which in turn promotes neural stem cell proliferation.
NUS Medicine and the EurekAlert release describe Arid2 and Ss18 as “helper genes” that open up DNA and activate other growth-related genes, and they report that neural stem cells lose the ability to renew without these helpers. ScienceDaily also describes the same general idea: DMTF1 regulates helper genes (Arid2 and Ss18) that loosen tightly packed DNA so growth-related genes can become active.
ScienceAlert reports that, while shorter telomeres seemed to contribute to lower DMTF1 levels, artificially boosting DMTF1 in cells did not change telomere length, suggesting the factor supports neuron production through another route. The Science Advances paper likewise notes that DMTF1 up-regulation rescued proliferation of telomere-dysfunctional neural stem cells and frames this as a potential target to reverse a proliferation defect modeled by telomere attrition.
What was tested
The NUS Medicine report says the study was led by Assistant Professor Ong Sek Tong Derrick, with Dr Liang Yajing as first author, and that the work aimed to identify biological factors influencing the degeneration of neural stem cell function associated with aging. The team assessed DMTF1’s role using neural stem cells derived from humans and laboratory models that simulate premature aging, and they used genome binding and transcriptome analyses to examine mechanisms.
The ScienceDaily report says the researchers examined neural stem cells derived from humans and from laboratory models designed to mimic premature aging, with a focus on cells affected by telomere dysfunction. It describes telomeres as protective chromosome ends that shorten each time a cell divides and notes telomere shortening as a marker of aging.
ScienceAlert describes the work as combining lab analysis of human neural stem cells with mouse model experiments to identify DMTF1’s role in neural stem cells. It also characterizes neural stem cells in later life as becoming more dormant, with cognitive decline “creeping in” as neuron production falls.
What happens next
NUS Medicine says the current findings largely stem from in vitro experiments and that the researchers plan to explore whether elevating DMTF1 can regenerate neural stem cell numbers and improve learning and memory in conditions involving telomere shortening and natural aging, while avoiding increased risk of brain tumours. The long-term goal described by NUS Medicine is to find small molecules that can enhance DMTF1 expression and activity to improve the function of aged neural stem cells.
ScienceAlert also cautions that the research is based on lab experiments and mouse models and says any suggestion that neuron production could be boosted still needs to be proven, while noting DMTF1’s link to cell growth and a concern that too much duplication could lead to cancer tumors. The Science Advances paper similarly describes DMTF1 as a potential therapeutic target to reverse the proliferation defect of aged neural stem cells modeled by telomere attrition, while framing the work as identifying a distinct genetic program controlled by DMTF1 in neural stem cells.
