Journal
FRONTIERS IN NEUROSCIENCE
Volume 16, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fnins.2022.919462
Keywords
astrocyte; gliogenesis; lineage reprogramming; neurogenesis; proliferation; proneural; Sox10; Ascl1
Categories
Funding
- Wellcome Trust [206410/Z/17/Z, FC001002]
- European Research Council (ERC) under the European Union [101021560]
- German Research Foundation [BE 4182/11-1, 357058359, CRC1080, 221828878]
- research initiative of RheinlandPfalz at the Johannes Gutenberg University Mainz (ReALity)
- Inneruniversitare Forschungsforderung Stufe I of the Johannes Gutenberg University Mainz
- Cancer Research United Kingdom
- Medical Research Council
- Human Frontiers Science Program (HFSP Long-Term Fellowship) [LT000646/2015]
- Sao Paulo Research Foundation (FAPESP) [2021/13515-5]
- European Research Council (ERC) [101021560] Funding Source: European Research Council (ERC)
- Wellcome Trust [206410/Z/17/Z] Funding Source: Wellcome Trust
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The proneural transcription factor Ascl1 is involved in neural fate decisions. It has been widely used to reprogram non-neuronal cells into neurons in vitro. However, this study found that, in vivo, Ascl1 only had very low efficiency in inducing neuronal reprogramming of glial cells in the postnatal mouse cerebral cortex. Instead, Ascl1 selectively enhanced the proliferation of oligodendrocyte progenitor cells (OPCs).
The proneural transcription factor Achaete-scute complex-like 1 (Ascl1) is a major regulator of neural fate decisions, implicated both in neurogenesis and oligodendrogliogenesis. Focusing on its neurogenic activity, Ascl1 has been widely used to reprogram non-neuronal cells into induced neurons. In vitro, Ascl1 induces efficient reprogramming of proliferative astroglia from the early postnatal cerebral cortex into interneuron-like cells. Here, we examined whether Ascl1 can similarly induce neuronal reprogramming of glia undergoing proliferation in the postnatal mouse cerebral cortex in vivo. Toward this goal, we targeted cortical glia during the peak of proliferative expansion (i.e., postnatal day 5) by injecting a retrovirus encoding for Ascl1 into the mouse cerebral cortex. In contrast to the efficient reprogramming observed in vitro, in vivo Ascl1-transduced glial cells were converted into doublecortin-immunoreactive neurons only with very low efficiency. However, we noted a drastic shift in the relative number of retrovirus-transduced Sox10-positive oligodendrocyte progenitor cells (OPCs) as compared to glial fibrillary acidic protein (GFAP)-positive astrocytes. Genetic fate mapping demonstrated that this increase in OPCs was not due to Ascl1-mediated astrocyte-to-OPC fate conversion. Rather, EdU incorporation experiments revealed that Ascl1 caused a selective increase in proliferative activity of OPCs, but not astrocytes. Our data indicate that rather than inducing neuronal reprogramming of glia in the early postnatal cortex, Ascl1 is a selective enhancer of OPC proliferation.
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