Researchers from Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital have identified specific genes that define neural stem and progenitor cells (NPCs) in the adult brain. Their study, published in Stem Cell Reports, also links mutations in some of these genes to human neurological conditions.
For much of the 20th century, scientists believed that the adult brain could not regenerate. However, it is now understood that neurogenesis, or the birth of new neurons, occurs in adults. This process offers possible new treatments for various neurological disorders. One ongoing challenge has been identifying NPCs due to their rarity and similarities with other brain cells.
“The site of adult neurogenesis is the dentate gyrus in the hippocampus, the center for learning and memory. Compared to other brain regions, this small area of the brain holds a sparse population of NPCs and their progeny,” said Dr. Mirjana Maletić-Savatić, professor of pediatrics – neurology at Baylor and investigator at Duncan NRI. “New neurons are made in this area every day and they participate in learning and memory as well as mood control. Understanding neurogenesis is important because it could lead to improving conditions such as dementia, learning disabilities, depression and other related neurological and mental health conditions.”
Identifying NPCs has been difficult because “these cells are so rare and look so much like their neighbors that it’s been difficult to pinpoint their unique genetic signature,” according to Dr. William T. Choi, co-first author on the study.
Dr. Zhandong Liu explained: “We thought that the identification of NPC-specific markers could be successfully achieved by combining computational and experimental approaches.”
The research team used a computational tool called Digital Sorting Algorithm (DSA) to analyze genetic data containing mixtures of cell types. “With DSA we sifted through complex genetic data to identify which genes are active in NPCs and find unique gene expression patterns, like genetic fingerprints, for these cells. Using this approach, we identified 129 genes that are highly active in NPCs in mice,” said Dr. Gerarda Cappuccio.
Dr. Choi noted an important finding: “The critical part of our discovery came when we cross-referenced these genes with human data... We found that 25 of these genes were already known to cause specific neurological diseases in humans when mutated. Even more exciting, we identified 15 new candidate genes that we anticipate are linked to previously unexplained neurological disorders in patients.”
“Our approach not only sheds light on the molecular architecture of NPCs but also provides a valuable resource for studying the links between neural stem cell biology and human disorders,” Cappuccio added.
The authors suggest that using simple computational frameworks can help reveal connections between genetics and disease biology relevant for patient care.
Other contributors include Fatih Semerci, Jill A. Rosenfeld, Toni Claire Tacorda, Guantong Qi, Anthony W. Zoghbi, Yi Zhong, Hu Chen and Pengfei Liu from institutions such as Baylor College of Medicine, Duncan NRI, Baylor Genetics laboratories and University of Houston.
Funding was provided by several organizations including grants from federal agencies such as the National Institute on Aging (1R01AG076942), Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD103555), Autism Speaks, Cynthia and Antony Petrello Endowment as well as training programs based at Baylor College of Medicine.
