2. Academic Validation
  3. Robust reprogramming of glia into neurons by inhibition of Notch signaling and nuclear factor I (NFI) factors in adult mammalian retina

Robust reprogramming of glia into neurons by inhibition of Notch signaling and nuclear factor I (NFI) factors in adult mammalian retina

  • Sci Adv. 2024 Jul 12;10(28):eadn2091. doi: 10.1126/sciadv.adn2091.
Nguyet Le 1,  Trieu-Duc Vu 2 3,  Isabella Palazzo 1,  Ritvik Pulya 1,  Yehna Kim 1,  Seth Blackshaw 1 4 5 6 7,  Thanh Hoang 2 3 8
Affiliations

Affiliations

  • 1 Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 2 Department of Ophthalmology and Visual Sciences, University of Michigan School of Medicine, Ann Arbor, MI 48105.
  • 3 Michigan Neuroscience Institute, University of Michigan School of Medicine, Ann Arbor, MI 48105, USA.
  • 4 Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 5 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 6 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 7 Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 8 Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48105, USA.
PMID: 38996013 DOI: 10.1126/sciadv.adn2091
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.

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