Discovery of new role of SOX2 protein sheds light on neurogenesis in the adult brain
Newborn neurons generated from neural progenitor cells in a brain region called the hippocampus play an important role in learning and memory in adults. However, the molecular mechanisms that control this neurogenesis process have not been fully understood. Sanford-Burnham researchers recently shed new light on this question by discovering a key role of a protein called SOX2 in neuronal development. As reported online in Proceedings of the National Academy of Sciences, SOX2 promotes the activation of genes involved in differentiation, enabling neural progenitor cells to turn into mature neurons in the brains of adult mice.
“Although SOX2 is arguably a cornerstone of neural stem cell biology and plays an essential role in neurogenesis in the developing and adult brain, the mechanisms by which this protein regulates neuronal differentiation have remained unclear until now,” said senior study author Alexey Terskikh, Ph.D., associate professor in the Development, Aging, and Regeneration Program at Sanford-Burnham. “Understanding the fundamental mechanism of SOX2 function may inspire the design of pharmacological approaches to enhance adult neurogenesis as well as shed light on the potential function of SOX2 in cancer stem cells.”
SOX2 supports cell survival SOX2 is a well-known marker of neural stem and progenitor cells, and its function is required for the self-renewal of these cells. SOX2 mutations are associated with defective hippocampal development and seizures in humans and impaired neurogenesis in the adult mouse brain. However, the molecular mechanisms underlying the function of SOX2 in adult neurogenesis were previously unknown. Past research has suggested that SOX2 binds to the regulatory regions of hundreds of genes involved in neuronal differentiation and represses their activity, but it has not been clear whether the protein might also contribute to the activation of these genes.
In the new study, Terskikh and his team found that SOX2 deficiency in neural progenitor cells in the hippocampus of adult mice reduced the activation of genes that are essential for neuronal differentiation. As a result, many new neurons died before maturation, while surviving newborn neurons had structural abnormalities and displayed unusual activity. SOX2 binds to the regulatory regions of these genes, called Ngn2 and NeuroD1, and prevents the accumulation of a gene-silencing epigenetic mark called H3K27me3. Taken together, the findings suggest that SOX2 promotes a poised epigenetic state at the regulatory regions of neurogenic genes, thereby enabling neural progenitor cells to turn into mature neurons upon exposure to molecular cues that trigger differentiation.
On a clinical note, the neuronal defects observed in the hippocampus of adult mice may contribute to the learning and intellectual disabilities experienced by patients with a rare disorder called SOX2 anophthalmia syndrome. “Given the reversibility of epigenetic changes, our results suggest that pharmacological therapies directed at restoring the levels of neurogenic genes down-regulated in SOX2-deficient neural progenitor cells in the hippocampus might be beneficial for anophthalmia syndrome patients, particularly in ameliorating hippocampal-related learning disability,” Terskikh said.
Broad clinical relevance Moving forward, the researchers will continue to investigate the newly discovered function of SOX2 and the impact of SOX2 deficiency on hippocampus-dependent learning and memory tasks. They will also identify other factors involved in the epigenetic regulation of differentiation genes by elucidating pathways and mechanisms of action downstream of SOX2 on the whole-genome scale.
Another clinically relevant research direction will be to further explore the role of SOX2 in cancer. Past research has shown that this protein maintains cancer stem cells, drives tumor initiation, and promotes resistance to cancer drugs. “The mechanisms of SOX2 function we discovered are likely to apply to other tissue stem cell compartments as well as to multiple types of cancer that overexpress SOX2 in cancer stem cells,” Terskikh said.
Terskikh and his team are currently using their findings to develop small-molecule inhibitors of cancer stem cells for the treatment of glioblastoma multiforme—a fast-growing type of malignant brain tumor that is the most common brain tumor in adults. “Because there are currently no effective long-term treatments for this disease, patients have a poor prognosis and usually survive less than 15 months following diagnosis,” Terskikh said. “Therapies that target SOX2 activity in cancer stem cells offer promise for eradicating these aggressive brain tumors and dramatically improving clinical outcomes for patients.”
Janelle Weaver, Ph.D., a freelance writer, contributed to this article.