We are interested in how systemic metabolism controls neurogenesis. Neurogenesis is a plastic, developmental process that is maintained in the adult brain. Adult neural stem cells in the hippocampus generate new neurons that play important roles in modulating memory and emotions. Reduced activity of adult hippocampal stem cells (AHSCs) is linked to impaired memory associated with ageing, and to affective and mood disorders, including depression. The production of new neurons is regulated by physiological, pathological and pharmacological stimuli, such as exercise, diet, stress or antidepressants. However, the mechanisms linking those stimuli to AHSCs remain unknown.
I have always been interested in neuroscience, and intrigued by how little we know about the way our brains work. At the same time, I am amazed by how a whole organism can derive from a single cell. During my PhD, I was lucky enough to unite my two passions and study neurodevelopmental biology. It was during that time that I learned more about stem cell biology and became interested in adult neural stem cells. How neurogenesis, such a plastic developmental process, is maintained in adult brains really struck me. It’s as if we still have a bit of development happening in our brains, continuously remodeling it. As a postdoc, I studied the intrinsic mechanisms controlling adult neural stem cells in the hippocampus. New neurons generated in this region play crucial roles in the modulation of high order functions, including memory and mood. We know that everyday actions such as exercise, exposure to a new environment or our diet have a great impact on adult neurogenesis. This is really important, because it means that by changing our behavior, we have the power to also change the way our brain is being remodeled. However, the links between such general stimuli and the regulation of AHSCs are still obscure.
We want to determine how systemic stimuli influence the signaling pathways that regulate AHSC activity. Alterations in metabolism are known to affect stem cells in other tissues. Intriguingly, metabolic disorders such as diabetes also have strong links with depression and cognitive disorders. Thus, our first goal is to address how changes in systemic metabolism affect AHSC function.
We use mouse models of ageing, diabetes and caloric restriction in combination with transgenic mice to monitor the behavior of AHSCs in response to metabolic changes. We are using in vivo genetic tools to label and/or disrupt specific genes in niche cells and then assess the response of stem cells, which will help us understand how AHSCs detect changes in their environment. We also explore the molecular mechanisms underlying the changes in AHSC behavior using in vitro models of murine and human neural stem cell quiescence. Finally, by using patient-derived lines we aim to elucidate how mutations and genetic variation affect human neural stem cell function. This in vitro approach also enables high-throughput screening to identify drugs that modulate adult neural stem cell functions. As a further tool to be able to investigate the interactions of the stem cells with the niche, we are increasing the complexity of our in vitro model by adding niche-like signals and structures, including 3D-scaffolding and local delivery of signaling molecules.
A better understanding of the crosstalk between metabolism and the regulation of the adult neural stem cell population will help us to predict and prevent neurological disorders, and perhaps even to devise strategies to reverse adult stem cell failure.
Urbán, N., Blomfield, IM., Guillemot, F. (2019). Quiescence of Adult Mammalian Neural Stem Cells: A Highly Regulated Rest. Neuron. 104(5):834-848
Blomfield, IM., Rocamonde, B., Masdeu, MDM., Mulugeta, E., Vaga, S., van den Berg, DL., Huillard, E., Guillemot, F., Urbán, N. (2019). Id4 promotes the elimination of the pro-activation factor Ascl1 to maintain quiescence of adult hippocampal stem cells. Elife. 8
Urbán, N., van den Berg, DL., Forget, A., Andersen, J., Demmers, JA., Hunt, C., Ayrault, O., Guillemot, F. (2016). Return to quiescence of mouse neural stem cells by degradation of a proactivation protein. Science. 353(6296):292-5
Urbán, N., Guillemot, F. (2014). Neurogenesis in the embryonic and adult brain: same regulators, different roles. Front Cell Neurosci. 8:396
Andersen, J., Urbán, N., Achimastou, A., Ito, A., Simic, M., Ullom, K., Martynoga, B., Lebel, M., Göritz, C., Frisén, J., Nakafuku, M., Guillemot, F. (2014). A transcriptional mechanism integrating inputs from extracellular signals to activate hippocampal stem cells. Neuron. 83(5):1085-97
Martynoga, B., Mateo, JL., Zhou, B., Andersen, J., Achimastou, A., Urbán, N., van den Berg, D., Georgopoulou, D., Hadjur, S., Wittbrodt, J., Ettwiller, L., Piper, M., Gronostajski, RM., Guillemot, F. (2013). Epigenomic enhancer annotation reveals a key role for NFIX in neural stem cell quiescence. Genes Dev. 27(16):1769-86
Webb, AE., Pollina, EA., Vierbuchen, T., Urbán, N., Ucar, D., Leeman, DS., Martynoga, B., Sewak, M., Rando, TA., Guillemot, F., Wernig, M., Brunet, A. (2013). FOXO3 shares common targets with ASCL1 genome-wide and inhibits ASCL1-dependent neurogenesis. Cell Rep. 4(3):477-91