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Stem and progenitor cells show diversity in early brain development, which probably contributes to later neuronal complexity in the adult cortex. This is according to a new study published in Science Advances on November 6th. Researchers at the Children’s National Hospital’s Center for Neuroscience Research (CNR) say this research expands existing ideas about brain development and could have a significant impact on clinical care for neurodevelopmental disorders in the future. The study was carried out in collaboration with a research team at Yale University led by Dr. med. Nenad Sestan performed.

“Our study offers a new look at the landscape of the developing brain. What we see are new complex cell families that are very early in development,” says Dr. Tarik Haydar, director of the CNR at Children’s National, who led the study. “Understanding the role of these cells in the formation of the cerebral cortex is now possible in a way that was not possible before.”

The cerebral cortex occurs early in development and is the seat of higher order cognition, social behavior, and motor control. While the rich neural diversity of the cerebral cortex and the brain in general is well documented, the origin of this variation is relatively little known.

“We have shown in our previous work that neurons generated from different classes of cortical stem and progenitor cells have different functional properties,” says William Tyler, Ph.D., a member of the CNR Research Faculty and co-first author of the Study. “One reason for this study was to go back and try to classify all of the different precursors so that we could eventually figure out how each contributes to the diversity of neurons in the adult brain.”

Using a preclinical model, the researchers were able to identify numerous groups of cortical stem and progenitor cells with different gene expression profiles. The team also found that these cells showed early signs of lineage diversification, likely caused by transcription priming. This process produces RNA from a mother cell in order to pass it on to its daughter cells for later protein production.

Using novel trajectory reconstruction methods, the team observed different developmental currents that connect progenitor cell types to specific excitatory neurons. After comparing the preclinical model dataset with a database of human cells, notable similarities were found, such as the surprising presence of basal radial glial cells (bRGCs) between species, an important type of progenitor cell previously believed to be primarily in the Primate brain.

“At a very high level, the study is important as we are directly testing a basic theory of brain development,” says Zhen Li, Ph.D., postdoctoral fellow of CNR Research and co-first author of the study. The results support the Protomap theory, which states that early stem and progenitor diversity paves the way for later neural diversity and cortical complexity. In addition, the results also have exciting translation potential.

“There is evidence that neurodevelopmental diseases affect different populations of neural stem cells differently,” says Dr. Li. “If we can better understand the complexities of these neural stem cells, the future of disease prevention and treatment will have enormous implications.”

“If we can understand how this early landscape is affected by disturbances, we can predict the resulting changes in cortical architecture and then very narrowly define the behavior of cell groups in these disturbances,” adds Dr. Haydar added. “If we can understand how the cortex normally achieves its complex architecture, we have important entry points for improving the clinical correspondence of a particular disorder and improving the quality of life.”

Future topics the researchers want to investigate include the effects of developmental changes on brain function, the origin and operational importance of bRGCs, and the activity, connections, and cognitive traits enabled by different families of neurons.

Discovery of the fate of cells Switching from neurons to astrocytes in the developing brain

More information:
“Transcriptional Priming as a Conserved Mechanism of Lineage Diversification in the Developing Mouse and Human Neocortex” Science Advances (2020).… .1126 / sciadv.abd2068 Provided by Children’s National Hospital

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