MADRID, 14 (EUROPA PRESS)
Research from the Cajal-CSIC Neuroscience Center in Madrid has discovered a new mechanism (the 'Sox5' gene) that controls how adult neural stem cells are generated during the development of the dentate gyrus, a region of the hippocampus involved in memory and learning.
The study, led by Dr. Aixa Morales, head of the Molecular Control of Neurogenesis Laboratory, was conducted in mice and focuses on these neural cells, which remain in a resting state known as quiescence. This state in which they are not mature cells nor do they divide to generate neurons, but in which they can be activated when necessary. This "resting" strategy ensures that they do not become exhausted prematurely.
What was not well understood until now was the mechanisms that ensure the proper and reversible entry into quiescence. Thus, this work demonstrates that the gene 'Sox5' is "crucial" for establishing this state of rest in a balanced manner, the authors state. Previous studies had shown that 'Sox5' is important for adult neurogenesis, and now, this research shows that it is also necessary for the formation of neural stem cells during the development of the dentate gyrus.
Furthermore, the results of the study published in 'PLOS Biology' also reveal that the BMP (Bone Morphogenetic Proteins) signaling pathway, which is key to embryonic development, is overactivated when Sox5 is missing. The BMP pathway promotes quiescence, and in the absence of Sox5, it is deregulated, preventing the necessary balance between stem cell quiescence and activation.
"By inhibiting this pathway with small molecules injected into mice lacking 'Sox5,' we were able to reverse some of the alterations caused by the loss of this gene in neural stem cells," explains Paula Tirado, a researcher at the Cajal Neuroscience Center and co-author of the study. Thus, this finding opens the door to possible therapeutic strategies aimed at modulating the BMP pathway in contexts of neuronal loss, such as aging or neurodegenerative diseases.
Another relevant finding is the identification of a "critical" time window during the second week after birth, in which the proper balance is established between two resting states of neural stem cells: a deep state that keeps them inactive for long periods, and a superficial state, in which they are closer to being activated.
During this time window, Sox5 limits the entry of superficially resting neural stem cells; an essential action to prevent a transient overproduction of neurons in youth, which could deplete the stem cell pool and therefore reduce the brain's regenerative capacity in adulthood, the authors note.
Furthermore, in humans, mutations in the SOX5 gene are linked to Lamb-Shaffer syndrome, a rare disease that manifests with language disorders, cognitive impairments, and autism spectrum traits. This new work offers a framework for delving deeper into the altered cellular mechanisms in these patients and exploring future treatment approaches, the study notes.
It also demonstrates the importance of unraveling the genetic keys that promote adult neurogenesis during development and opens the door to designing strategies to activate neural stem cells in situations of neuronal loss, as occurs in neurodegenerative diseases, he concludes.
