Inducing Different Neuronal Subtypes from Astrocytes in the Injured Mouse Cerebral Cortex

• Published in: Neuron (Cambridge, Mass.) Mass.), 2019-09, Vol.103 (6), p.1086-1095.e5
• Main Authors: Mattugini, Nicola, Bocchi, Riccardo, Scheuss, Volker, Russo, Gianluca Luigi, Torper, Olof, Lao, Chu Lan, Götz, Magdalena
• Format: Article
• Language: English
• Subjects: AAV; Animals; Astrocytes; Astrocytes - cytology; Astrocytes - metabolism; axonal projection; Basic Helix-Loop-Helix Transcription Factors - genetics; Brain Injuries, Traumatic; Cellular Reprogramming Techniques - methods; Cerebral cortex; Cerebral Cortex - cytology; Cerebral Cortex - injuries; cortical layers; Dependovirus; electrophysiology; Experiments; Gene expression; Genetic Vectors; Gliosis; Gray Matter - cytology; inflammation; lentivirus; Mice; Morphology; Nerve Tissue Proteins - genetics; Neurogenins; Neurons; Neurons - cytology; Neurons - metabolism; Nuclear Receptor Subfamily 4, Group A, Member 2 - genetics; Nuclear receptors; Nurr1 protein; Pyramidal Cells - cytology; Pyramidal Cells - metabolism; reactive gliosis; reprogramming; Substantia alba; Substantia grisea; Transcription factors; Vectors (Biology); White Matter - cytology; Wounds, Stab
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2019.08.009

Astrocytes are particularly promising candidates for reprogramming into neurons, as they maintain some of the original patterning information from their radial glial ancestors. However, to which extent the position of astrocytes influences the fate of reprogrammed neurons remains unknown. To elucidate this, we performed stab wound injury covering an entire neocortical column, including the gray matter (GM) and white matter (WM), and targeted local reactive astrocytes via injecting FLEx switch (Cre-On) adeno-associated viral (AAV) vectors into mGFAP-Cre mice. Single proneural factors were not sufficient for adequate reprogramming, although their combination with the nuclear receptor-related 1 protein (Nurr1) improved reprogramming efficiency. Nurr1 and Neurogenin 2 (Ngn2) resulted in high-efficiency reprogramming of targeted astrocytes into neurons that develop lamina-specific hallmarks, including the appropriate long-distance axonal projections. Surprisingly, in the WM, we did not observe any reprogrammed neurons, thereby unveiling a crucial role of region- and layer-specific differences in astrocyte reprogramming. [Display omitted] •AAV can be targeted to reactive astrocytes upon stab wound injury•Expression of Ngn2 and Nurr1 in these astrocytes induces pyramidal neurons•Induced pyramidal neurons acquire correct layer identity and axonal projections•Neurons cannot be induced in the white matter Neurons dying after brain injury cannot be replaced. Mattugini, Bocchi, et al. show that local astrocytes can be converted into functional neurons acquiring appropriate layer identity and connectivity by expression of neurogenic factors in a mouse model of traumatic brain injury.