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Inducing Neural Regeneration from Glia Using Proneural bHLH Transcription Factors

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Retinal Degenerative Diseases XIX

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1415))

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Abstract

Endogenous regeneration strategies to replace lost neurons hold great promise for treating neurodegenerative disorders. In the majority of cases, neural regeneration is induced by converting resident glial cells into neurogenic precursors. This review will outline how proneural bHLH transcription factors can be used to reprogram glia in the brain and retina into a source for new neurons.

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References

  1. Baker NE, Brown NL. All in the family: proneural bHLH genes and neuronal diversity. Development. 2018;145:dev159426.

    PubMed  PubMed Central  Google Scholar 

  2. Bassett EA, Wallace VA. Cell fate determination in the vertebrate retina. Trends Neurosci. 2012;35:565–73.

    CAS  PubMed  Google Scholar 

  3. Ben-Arie N, Bellen HJ, Armstrong DL, McCall AE, Gordadze PR, Guo Q, Matzuk MM, Zoghbi HY. Math1 is essential for genesis of cerebellar granule neurons. Nature. 1997;390:169–72.

    CAS  PubMed  Google Scholar 

  4. Berninger B, Costa MR, Koch U, Schroeder T, Sutor B, Grothe B, Gotz M. Functional properties of neurons derived from in vitro reprogrammed postnatal astroglia. J Neurosci. 2007;27:8654–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Bertrand N, Castro DS, Guillemot F. Proneural genes and the specification of neural cell types. Nat Rev Neurosci. 2002;3:517–30.

    CAS  PubMed  Google Scholar 

  6. Blackshaw S, Sanes JR. Turning lead into gold: reprogramming retinal cells to cure blindness. J Clin Invest. 2021;131:e146134.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Bringmann A, Iandiev I, Pannicke T, Wurm A, Hollborn M, Wiedemann P, Osborne NN, Reichenbach A. Cellular signaling and factors involved in Muller cell gliosis: neuroprotective and detrimental effects. Prog Retin Eye Res. 2009;28:423–51.

    CAS  PubMed  Google Scholar 

  8. Brown NL, Patel S, Brzezinski J, Glaser T. Math5 is required for retinal ganglion cell and optic nerve formation. Development. 2001;128:2497–508.

    CAS  PubMed  Google Scholar 

  9. Brzezinski JAT, Prasov L, Glaser T. Math5 defines the ganglion cell competence state in a subpopulation of retinal progenitor cells exiting the cell cycle. Dev Biol. 2012;365:395–413.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen YC, Ma NX, Pei ZF, Wu Z, Do-Monte FH, Keefe S, Yellin E, Chen MS, Yin JC, Lee G, et al. A NeuroD1 AAV-based gene therapy for functional brain repair after ischemic injury through in vivo astrocyte-to-neuron conversion. Mol Ther. 2020;28:217–34.

    CAS  PubMed  Google Scholar 

  11. Gascon S, Murenu E, Masserdotti G, Ortega F, Russo GL, Petrik D, Deshpande A, Heinrich C, Karow M, Robertson SP, et al. Identification and successful negotiation of a metabolic checkpoint in direct neuronal reprogramming. Cell Stem Cell. 2016;18:396–409.

    CAS  PubMed  Google Scholar 

  12. Goldman D. Muller glial cell reprogramming and retina regeneration. Nat Rev Neurosci. 2014;15:431–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Gotz M, Bocchi R. Neuronal replacement: concepts, achievements, and call for caution. Curr Opin Neurobiol. 2021;69:185–92.

    PubMed  PubMed Central  Google Scholar 

  14. Grande A, Sumiyoshi K, Lopez-Juarez A, Howard J, Sakthivel B, Aronow B, Campbell K, Nakafuku M. Environmental impact on direct neuronal reprogramming in vivo in the adult brain. Nat Commun. 2013;4:2373.

    PubMed  Google Scholar 

  15. Guillemot F. Cell fate specification in the mammalian telencephalon. Prog Neurobiol. 2007;83:37–52.

    CAS  PubMed  Google Scholar 

  16. Guillemot F, Hassan BA. Beyond proneural: emerging functions and regulations of proneural proteins. Curr Opin Neurobiol. 2017;42:93–101.

    CAS  PubMed  Google Scholar 

  17. Guo Z, Zhang L, Wu Z, Chen Y, Wang F, Chen G. In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Cell Stem Cell. 2014;14:188–202.

    CAS  PubMed  Google Scholar 

  18. Heinrich C, Bergami M, Gascon S, Lepier A, Vigano F, Dimou L, Sutor B, Berninger B, Gotz M. Sox2-mediated conversion of NG2 glia into induced neurons in the injured adult cerebral cortex. Stem Cell Rep. 2014;3:1000–14.

    CAS  Google Scholar 

  19. Herrero-Navarro A, Puche-Aroca L, Moreno-Juan V, Sempere-Ferrandez A, Espinosa A, Susin R, Torres-Masjoan L, Leyva-Diaz E, Karow M, Figueres-Onate M, et al. Astrocytes and neurons share region-specific transcriptional signatures that confer regional identity to neuronal reprogramming. Sci Adv. 2021;7:eabe8978.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Hoang T, Wang J, Boyd P, Wang F, Santiago C, Jiang L, Yoo S, Lahne M, Todd LJ, Jia M, et al. Gene regulatory networks controlling vertebrate retinal regeneration. Science. 2020;370:eabb8598.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Imayoshi I, Kageyama R. bHLH factors in self-renewal, multipotency, and fate choice of neural progenitor cells. Neuron. 2014;82:9–23.

    CAS  PubMed  Google Scholar 

  22. Jorstad NL, Wilken MS, Grimes WN, Wohl SG, VandenBosch LS, Yoshimatsu T, Wong RO, Rieke F, Reh TA. Stimulation of functional neuronal regeneration from Muller glia in adult mice. Nature. 2017;548:103–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Jorstad NL, Wilken MS, Todd L, Finkbeiner C, Nakamura P, Radulovich N, Hooper MJ, Chitsazan A, Wilkerson BA, Rieke F, et al. STAT signaling modifies Ascl1 chromatin binding and limits neural regeneration from Muller glia in adult mouse retina. Cell Rep. 2020;30:2195–2208.e5.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Lentini C, d’Orange M, Marichal N, Trottmann MM, Vignoles R, Foucault L, Verrier C, Massera C, Raineteau O, Conzelmann KK, et al. Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy. Cell Stem Cell. 2021;28:2104–2121.e10.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Liu Y, Miao Q, Yuan J, Han S, Zhang P, Li S, Rao Z, Zhao W, Ye Q, Geng J, et al. Ascl1 converts dorsal midbrain astrocytes into functional neurons in vivo. J Neurosci. 2015;35:9336–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Lust K, Sinn R, Perez Saturnino A, Centanin L, Wittbrodt J. De novo neurogenesis by targeted expression of atoh7 to Muller glia cells. Development. 2016;143:1874–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Masserdotti G, Gillotin S, Sutor B, Drechsel D, Irmler M, Jorgensen HF, Sass S, Theis FJ, Beckers J, Berninger B, et al. Transcriptional mechanisms of proneural factors and REST in regulating neuronal reprogramming of astrocytes. Cell Stem Cell. 2015;17:74–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Mattugini N, Bocchi R, Scheuss V, Russo GL, Torper O, Lao CL, Gotz M. Inducing different neuronal subtypes from astrocytes in the injured mouse cerebral cortex. Neuron. 2019;103:1086–1095.e5.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ng AHM, Khoshakhlagh P, Rojo Arias JE, Pasquini G, Wang K, Swiersy A, Shipman SL, Appleton E, Kiaee K, Kohman RE, et al. A comprehensive library of human transcription factors for cell fate engineering. Nat Biotechnol. 2021;39:510–9.

    CAS  PubMed  Google Scholar 

  30. Pereira M, Birtele M, Shrigley S, Benitez JA, Hedlund E, Parmar M, Ottosson DR. Direct reprogramming of resident NG2 glia into neurons with properties of fast-spiking parvalbumin-containing interneurons. Stem Cell Rep. 2017;9:742–51.

    CAS  Google Scholar 

  31. Pollak J, Wilken MS, Ueki Y, Cox KE, Sullivan JM, Taylor RJ, Levine EM, Reh TA. ASCL1 reprograms mouse Muller glia into neurogenic retinal progenitors. Development. 2013;140:2619–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Schuurmans C, Armant O, Nieto M, Stenman JM, Britz O, Klenin N, Brown C, Langevin LM, Seibt J, Tang H, et al. Sequential phases of cortical specification involve Neurogenin-dependent and -independent pathways. EMBO J. 2004;23:2892–902.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Stern JH, Tian Y, Funderburgh J, Pellegrini G, Zhang K, Goldberg JL, Ali RR, Young M, Xie Y, Temple S. Regenerating eye tissues to preserve and restore vision. Cell Stem Cell. 2018;23:453.

    CAS  PubMed  Google Scholar 

  34. Todd L, Reh TA. Comparative biology of vertebrate retinal regeneration: restoration of vision through cellular reprogramming. Cold Spring Harb Perspect Biol. 2021;14:a040816.

    Google Scholar 

  35. Todd L, Finkbeiner C, Wong CK, Hooper MJ, Reh TA. Microglia suppress Ascl1-induced retinal regeneration in mice. Cell Rep. 2020;33:108507.

    CAS  PubMed  Google Scholar 

  36. Todd L, Hooper MJ, Haugan AK, Finkbeiner C, Jorstad N, Radulovich N, Wong CK, Donaldson PC, Jenkins W, Chen Q, et al. Efficient stimulation of retinal regeneration from Muller glia in adult mice using combinations of proneural bHLH transcription factors. Cell Rep. 2021;37:109857.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Torper O, Pfisterer U, Wolf DA, Pereira M, Lau S, Jakobsson J, Bjorklund A, Grealish S, Parmar M. Generation of induced neurons via direct conversion in vivo. Proc Natl Acad Sci U S A. 2013;110:7038–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Torper O, Ottosson DR, Pereira M, Lau S, Cardoso T, Grealish S, Parmar M. In vivo reprogramming of striatal NG2 glia into functional neurons that integrate into local host circuitry. Cell Rep. 2015;12:474–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Ueki Y, Wilken MS, Cox KE, Chipman L, Jorstad N, Sternhagen K, Simic M, Ullom K, Nakafuku M, Reh TA. Transgenic expression of the proneural transcription factor Ascl1 in Muller glia stimulates retinal regeneration in young mice. Proc Natl Acad Sci U S A. 2015;112:13717–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang LL, Serrano C, Zhong X, Ma S, Zou Y, Zhang CL. Revisiting astrocyte to neuron conversion with lineage tracing in vivo. Cell. 2021;184:5465–5481.e16.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Zamboni M, Llorens-Bobadilla E, Magnusson JP, Frisen J. A widespread neurogenic potential of neocortical astrocytes is induced by injury. Cell Stem Cell. 2020;27:605–617.e5.

    CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Biological Structure, University of Washington, Seattle, WA, USA

    Levi Todd

Authors
  1. Levi Todd
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Correspondence to Levi Todd .

Editor information

Editors and Affiliations

  1. Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    John D. Ash

  2. Ocular Genomics InstituteDepartment of OphthalmologyMassachusetts Eye and Ear InfirmaryHarvard Medical School, Boston, MA, USA

    Eric Pierce

  3. Health Sciences Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Robert E. Anderson

  4. Department of Ophthalmology, Duke Medical Center, Durham, NC, USA

    Catherine Bowes Rickman

  5. Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA

    Joe G. Hollyfield

  6. Laboratory for Retinal Cell BiologyDepartment of OphthalmologyUniversity Hospital Zurich, University of Zurich, Schlieren, Switzerland

    Christian Grimm

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Todd, L. (2023). Inducing Neural Regeneration from Glia Using Proneural bHLH Transcription Factors. In: Ash, J.D., Pierce, E., Anderson, R.E., Bowes Rickman, C., Hollyfield, J.G., Grimm, C. (eds) Retinal Degenerative Diseases XIX. Advances in Experimental Medicine and Biology, vol 1415. Springer, Cham. https://doi.org/10.1007/978-3-031-27681-1_84

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