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Robust reprogramming of glia into neurons by inhibition of Notch signaling and nuclear factor I (NFI) factors in adult mammalian retina.
- Source :
-
Science advances [Sci Adv] 2024 Jul 12; Vol. 10 (28), pp. eadn2091. Date of Electronic Publication: 2024 Jul 12. - Publication Year :
- 2024
-
Abstract
- Generation of neurons through direct reprogramming has emerged as a promising therapeutic approach for treating neurodegenerative diseases. In this study, we present an efficient method for reprogramming retinal glial cells into neurons. By suppressing Notch signaling by disrupting either Rbpj or Notch1/2 , we induced mature Müller glial cells to reprogram into bipolar- and amacrine-like neurons. We demonstrate that Rbpj directly activates both Notch effector genes and genes specific to mature Müller glia while indirectly repressing expression of neurogenic basic helix-loop-helix (bHLH) factors. Combined loss of function of Rbpj and Nfia/b/x resulted in conversion of nearly all Müller glia to neurons. Last, inducing Müller glial proliferation by overexpression of dominant-active Yap promotes neurogenesis in both Rbpj - and Nfia/b/x/Rbpj -deficient Müller glia. These findings demonstrate that Notch signaling and NFI factors act in parallel to inhibit neurogenic competence in mammalian Müller glia and help clarify potential strategies for regenerative therapies aimed at treating retinal dystrophies.
- Subjects :
- Animals
Mice
Immunoglobulin J Recombination Signal Sequence-Binding Protein metabolism
Immunoglobulin J Recombination Signal Sequence-Binding Protein genetics
Neurogenesis
YAP-Signaling Proteins metabolism
Cell Proliferation
NFI Transcription Factors metabolism
NFI Transcription Factors genetics
Signal Transduction
Cellular Reprogramming
Retina metabolism
Retina cytology
Ependymoglial Cells metabolism
Ependymoglial Cells cytology
Neuroglia metabolism
Receptors, Notch metabolism
Neurons metabolism
Neurons cytology
Subjects
Details
- Language :
- English
- ISSN :
- 2375-2548
- Volume :
- 10
- Issue :
- 28
- Database :
- MEDLINE
- Journal :
- Science advances
- Publication Type :
- Academic Journal
- Accession number :
- 38996013
- Full Text :
- https://doi.org/10.1126/sciadv.adn2091