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Direct in vivo Glia-To-Neuron conversion in the postnatal mouse cerebral cortex

CRTD Seminar

Date:16.01.2019, 14:00 - 15:00
Speaker: Dr. Sophie Péron, Adult Neurogenesis & Cellular Reprogramming, Institute of Physiological Chemistry, University Medical Center, Johannes Gutenberg University Mainz & Center for Developmental Neurobiology
Location: CRTD, auditorium left
Host: Prof. Federico Calegari

Abstract
Brain-resident glial cells can be directly reprogrammed into neurons in vivo by forced expression of neurogenic transcription factors. In the adult mouse cortex, such fate switch was reported to occur only following brain lesion (Heinrich et al., 2014), which is known to elicit local glial proliferation. To clarify the influence of the proliferative state of glia on the reprogramming process, we tested whether proliferative glia can be lineage converted in vivo in the absence of a prior lesion in the postnatal mouse cortex.
Glial cells proliferate locally in the early postnatal cortex (Ge et al., 2012). To target these cells for lineage conversion we injected retroviruses encoding for neurogenic transcription factors in the cortex of postnatal mice. Noticeably, overexpression of Ascl1, Neurog2 or NeuroD1 alone was inefficient in inducing glia-to-neuron conversion. We thus tested whether synergism with other molecular pathways could induce reprogramming (Gascón et al., 2016; Heinrich et al., 2014; Karow et al., 2018). Interestingly, we observed that Sox2 or Bcl2 co-expression together with Ascl1 converted glial cells into neurons, some of which expressed the inhibitory neurotransmitter GABA. Likewise, we show that Bcl2 can enhance Neurog2-mediated glia-to-neuron conversion. Remarkably, the combined expression of these two factors not only dramatically raised the conversion efficiency, but also gave rise to neurons exhibiting a highly elaborated neuronal morphology, bearing dendritic spines and developing long-distance projections. BrdU incorporation assay confirmed the proliferative state of converted cells at the time of viral infection. The functional integration and electrophysiological properties of the reprogrammed cells is currently being investigated.

This work was supported by grants of the Wellcome Trust, DFG, and BMBF (NEURON ERA-NET ImprovVision) to BB, and the Bavarian State Ministry of Education, Science and the Arts to MK. NM was supported by the Human Frontier Science Program.

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