1. Reprogramming astroglia into neurons with hallmarks of fast-spiking parvalbumin-positive interneurons by phospho-site-deficient Ascl1.
- Author
-
Marichal N, Péron S, Beltrán Arranz A, Galante C, Franco Scarante F, Wiffen R, Schuurmans C, Karow M, Gascón S, and Berninger B
- Subjects
- Animals, Mice, Neurons metabolism, Neurons cytology, Action Potentials, Phosphorylation, Cell Differentiation, Basic Helix-Loop-Helix Transcription Factors metabolism, Basic Helix-Loop-Helix Transcription Factors genetics, Astrocytes metabolism, Astrocytes cytology, Cellular Reprogramming, Interneurons metabolism, Parvalbumins metabolism
- Abstract
Cellular reprogramming of mammalian glia to an induced neuronal fate holds the potential for restoring diseased brain circuits. While the proneural factor achaete-scute complex-like 1 ( Ascl1 ) is widely used for neuronal reprogramming, in the early postnatal mouse cortex, Ascl1 fails to induce the glia-to-neuron conversion, instead promoting the proliferation of oligodendrocyte progenitor cells (OPC). Since Ascl1 activity is posttranslationally regulated, here, we investigated the consequences of mutating six serine phospho-acceptor sites to alanine (Ascl1SA6) on lineage reprogramming in vivo. Ascl1SA6 exhibited increased neurogenic activity in the glia of the early postnatal mouse cortex, an effect enhanced by coexpression of B cell lymphoma 2 ( Bcl2 ). Genetic fate-mapping revealed that most induced neurons originated from astrocytes, while only a few derived from OPCs. Many Ascl1SA6/Bcl2-induced neurons expressed parvalbumin and were capable of high-frequency action potential firing. Our study demonstrates the authentic conversion of astroglia into neurons featuring subclass hallmarks of cortical interneurons, advancing our scope of engineering neuronal fates in the brain.
- Published
- 2024
- Full Text
- View/download PDF