| Project Detail |
From glial cell to neuron: reprogramming via transcription factors
Until a couple decades ago, scientists believed glial cells, including astrocytes, did not serve any function other than structural, acting like a ‘glue’ that holds the neurons together. We now know this heterogeneous population of cells plays important roles in modulating nervous system function, its development and in protecting it or aiding in recovery. Recently, the discovery that endogenous glial cells can be reprogrammed into functional neurons has offered new hope for recovery of neuronal loss after injury or disease. With the support of the Marie Sklodowska-Curie Actions programme, the CELLIDRECUT project will investigate the potential of so-called Onecut transcription factors to reprogramme in vivo astrocytes into functional neurons.
Neuronal loss is at the core of cognitive and functional failures of both acute brain injuries and neurodegenerative diseases. Direct neuronal reprogramming of local glial cells is emerging as a promising approach for restorative brain therapy. However, in order to use direct glia-to-neuron reprogramming for the treatment of neuronal loss we still need to address a number of challenges, namely reliable and long-term conversion into the desired neuron subtype. In this proposal we aim to generate specific neuronal subtypes using novel fate determinants in glia-to-neuron reprogramming, and to provide a detailed molecular analysis of the newly generated neurons over time. Our data indicate that ONECUT factors may represent excellent novel candidates for astrocyte reprogramming into neuronal fates. To address this possibility, in this proposal we will focus on the thalamocortical system, which represents the main input to the neocortex and it is essential to cortical processing. We hypothesize that the innovative combination of nuclei specific thalamic factors with ONECUT factors could reveal new avenues for the direct reprogramming of astrocytes into thalamic neurons of specific sensory modalities and may inform future strategies for brain repair. Here, we have unique expertise and molecular tools at hand that will allow us to reprogram astrocytes into specific neuron types in vitro and in vivo. Moreover, as our ultimate goal is to reprogram astrocytes to recover neuronal loss, we will test whether astrocytes from a sensory deprived thalamus can be reprogrammed. By using state-of-the-art techniques such as 3D light-sheet microscopy, calcium imaging and transcriptomic analysis, we will determine the fidelity and functionality of the newly generated neurons. This approach will offer us unparalleled advantages for the discovery of novel reprogramming combinations and address important questions about reliable and long-term conversion into the desired neuron type. |
