Final Activity Report Summary - NSCMAIN (Identification of Signalling Pathways Controlling Adult Neural Stem Cell Maintenance)
The hippocampus is a brain region, which is essential for learning and memory formation. One of the most exciting discoveries of the past decade was the finding that new neurons are continuously generated in the hippocampus throughout adulthood and that this process -which is also termed hippocampal neurogenesis - is important for hippocampal function. The importance of hippocampal neurogenesis is illustrated by the fact that age-related memory dysfunction is paralleled by a strong decrease in the generation of new neurons.
New neurons originate from neural stem cells. These neural stem cells are immature cells, which have the ability to self-renew and to generate new neural stem cells on the one hand and to differentiate into neurons on the other hand. To ensure that hippocampal neurogenesis persists throughout adulthood self-renewal and differentiation have to be balanced. The objective of this project was to identify signals that control this balance. We have found several signals that are involved in the differentiation of neural stem cells into neurons. Among these are the transcription factors CREB and Sox11. Loss of CREB-function results in the loss of survival and differentiation, while gain of Sox11-function was sufficient to enhance neuronal differentiation of neural stem cells. We also identified a signalling pathway that regulates neural stem cell maintenance. Loss of this signal resulted in the increased differentiation of neural stem cells and consequently to a depletion of the neural stem cell pool.
It has been estimated that because of a greatly increased average life span, the percentage of individuals older than 65 years will almost double during the next 30 years from approximately 15 % to 25 %. The concomitant rise in the prevalence of age-related diseases such as impairment of cognitive function and dementia (the extreme form of cognitive impairment) poses an increasing challenge to society and public health, and demands the development of new treatment strategies for these currently intractable diseases. Given the mounting evidence for a link between adult hippocampal neurogenesis and cognitive function, these results may significantly contribute to the design of novel therapeutic approaches to age-related cognitive impairment and dementia.
New neurons originate from neural stem cells. These neural stem cells are immature cells, which have the ability to self-renew and to generate new neural stem cells on the one hand and to differentiate into neurons on the other hand. To ensure that hippocampal neurogenesis persists throughout adulthood self-renewal and differentiation have to be balanced. The objective of this project was to identify signals that control this balance. We have found several signals that are involved in the differentiation of neural stem cells into neurons. Among these are the transcription factors CREB and Sox11. Loss of CREB-function results in the loss of survival and differentiation, while gain of Sox11-function was sufficient to enhance neuronal differentiation of neural stem cells. We also identified a signalling pathway that regulates neural stem cell maintenance. Loss of this signal resulted in the increased differentiation of neural stem cells and consequently to a depletion of the neural stem cell pool.
It has been estimated that because of a greatly increased average life span, the percentage of individuals older than 65 years will almost double during the next 30 years from approximately 15 % to 25 %. The concomitant rise in the prevalence of age-related diseases such as impairment of cognitive function and dementia (the extreme form of cognitive impairment) poses an increasing challenge to society and public health, and demands the development of new treatment strategies for these currently intractable diseases. Given the mounting evidence for a link between adult hippocampal neurogenesis and cognitive function, these results may significantly contribute to the design of novel therapeutic approaches to age-related cognitive impairment and dementia.