1932

Abstract

A holy grail of regenerative medicine is to replenish the cells that are lost due to disease. The adult mammalian central nervous system (CNS) has, however, largely lost such a regenerative ability. An emerging strategy for the generation of new neurons is through glia-to-neuron (GtN) conversion in vivo, mainly accomplished by the regulation of fate-determining factors. When inhibited, PTBP1, a factor involved in RNA biology, was reported to induce rapid and efficient GtN conversion in multiple regions of the adult CNS. Remarkably, PTBP1 inhibition was also claimed to greatly improve behaviors of mice with neurological diseases or aging. These phenomenal claims, if confirmed, would constitute a significant advancement in regenerative medicine. Unfortunately, neither GtN conversion nor therapeutic potential via PTBP1 inhibition was validated by the results of multiple subsequent replication studies with stringent methods. Here we review these controversial studies and conclude with recommendations for examining GtN conversion in vivo and future investigations of PTBP1.

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/content/journals/10.1146/annurev-neuro-092822-083410
2023-07-10
2024-12-07
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Literature Cited

  1. Ashiya M, Grabowski PJ. 1997. A neuron-specific splicing switch mediated by an array of pre-mRNA repressor sites: evidence of a regulatory role for the polypyrimidine tract binding protein and a brain-specific PTB counterpart. RNA 3:996–1015
    [Google Scholar]
  2. Barker RA, Götz M, Parmar M. 2018. New approaches for brain repair—from rescue to reprogramming. Nature 557:329–34
    [Google Scholar]
  3. Black DL. 2003. Mechanisms of alternative pre-messenger RNA splicing. Annu. Rev. Biochem. 72:291–336
    [Google Scholar]
  4. Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P et al. 2006. Muller cells in the healthy and diseased retina. Prog. Retin. Eye Res. 25:397–424
    [Google Scholar]
  5. Busch A, Hertel KJ. 2012. Evolution of SR protein and hnRNP splicing regulatory factors. Wiley Interdiscip. Rev. RNA 3:1–12
    [Google Scholar]
  6. Calzolari F, Berninger B 2021. cAAVe phaenomena: Beware of appearances!. Cell 184:5303–5
    [Google Scholar]
  7. Chan KY, Jang MJ, Yoo BB, Greenbaum A, Ravi N et al. 2017. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat. Neurosci. 20:1172–79
    [Google Scholar]
  8. Chen G, Wernig M, Berninger B, Nakafuku M, Parmar M, Zhang CL. 2015. In vivo reprogramming for brain and spinal cord repair. eNeuro 2:ENEURO.0106–15.2015
    [Google Scholar]
  9. Chen W, Zheng Q, Huang Q, Ma S, Li M 2022. Repressing PTBP1 fails to convert reactive astrocytes to dopaminergic neurons in a 6-hydroxydopamine mouse model of Parkinson's disease. eLife 11:e75636
    [Google Scholar]
  10. Corrionero A, Valcarcel J. 2009. RNA processing: redrawing the map of charted territory. Mol. Cell 36:918–19
    [Google Scholar]
  11. Gascón S, Murenu E, Masserdotti G, Ortega F, Russo GL et al. 2016. Identification and successful negotiation of a metabolic checkpoint in direct neuronal reprogramming. Cell Stem. Cell 18:396–409
    [Google Scholar]
  12. Grande A, Sumiyoshi K, López-Juárez A, Howard J, Sakthivel B et al. 2013. Environmental impact on direct neuronal reprogramming in vivo in the adult brain. Nat. Commun. 4:2373
    [Google Scholar]
  13. Guo T, Pan X, Jiang G, Zhang D, Qi J et al. 2022a. Downregulating PTBP1 fails to convert astrocytes into hippocampal neurons and to alleviate symptoms in Alzheimer's mouse models. J. Neurosci. 42:7309–17
    [Google Scholar]
  14. Guo T, Pan X, Jiang G, Zhang D, Qi J et al. 2022b. Downregulating PTBP1 fails to convert astrocytes into hippocampal neurons and to alleviate symptoms in Alzheimer's mouse models. bioRxiv 2022.04.27.489696. https://doi.org/10.1101/2022.04.27.489696
  15. Guo Z, Zhang L, Wu Z, Chen Y, Wang F, Chen G 2014. In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer's disease model. Cell Stem Cell 14:188–202
    [Google Scholar]
  16. Heinrich C, Bergami M, Gascón S, Lepier A, Viganò F et al. 2014. Sox2-mediated conversion of NG2 glia into induced neurons in the injured adult cerebral cortex. Stem Cell Rep. 3:1000–14
    [Google Scholar]
  17. Heinrich C, Spagnoli FM, Berninger B. 2015. In vivo reprogramming for tissue repair. Nat. Cell Biol. 17:204–11
    [Google Scholar]
  18. Hoang T, Kim DW, Appel H, Pannullo NA, Leavey P et al. 2021. Ptbp1 deletion does not induce glia-to-neuron conversion in adult mouse retina and brain. bioRxiv 2021.10.04.462784. https://doi.org/10.1101/2021.10.04.462784
    [Crossref]
  19. Hoang T, Kim DW, Appel H, Pannullo NA, Leavey P et al. 2022. Genetic loss of function of Ptbp1 does not induce glia-to-neuron conversion in retina. Cell Rep. 39:110849
    [Google Scholar]
  20. Hoang T, Wang J, Boyd P, Wang F, Santiago C et al. 2020. Gene regulatory networks controlling vertebrate retinal regeneration. Science 370:abb8598
    [Google Scholar]
  21. Hu J, Qian H, Xue Y, Fu XD. 2018. PTB/nPTB: master regulators of neuronal fate in mammals. Biophys. Rep. 4:204–14
    [Google Scholar]
  22. Islam MM, Smith DK, Niu W, Fang S, Iqbal N et al. 2015. Enhancer analysis unveils genetic interactions between TLX and SOX2 in neural stem cells and in vivo reprogramming. Stem Cell Rep. 5:805–15
    [Google Scholar]
  23. Jorstad NL, Wilken MS, Grimes WN, Wohl SG, VandenBosch LS et al. 2017. Stimulation of functional neuronal regeneration from Muller glia in adult mice. Nature 548:103–7
    [Google Scholar]
  24. Le N, Appel H, Pannullo N, Hoang T, Blackshaw S. 2022. Ectopic insert-dependent neuronal expression of GFAP promoter-driven AAV constructs in adult mouse retina. bioRxiv 2022.04.06.487191. https://doi.org/10.1101/2022.04.06.487191
    [Crossref]
  25. Leib D, Chen YH, Monteys AM, Davidson BL. 2022. Limited astrocyte-to-neuron conversion in the mouse brain using NeuroD1 overexpression. Mol. Ther. 30:982–86
    [Google Scholar]
  26. Lentini C, d'Orange M, Marichal N, Trottmann MM, Vignoles R et al. 2021. Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy. Cell Stem Cell 28:2104–21.e10
    [Google Scholar]
  27. Lillevali K, Kulla A, Ord T. 2001. Comparative expression analysis of the genes encoding polypyrimidine tract binding protein (PTB) and its neural homologue (brPTB) in prenatal and postnatal mouse brain. Mech. Dev. 101:217–20
    [Google Scholar]
  28. Maimon R, Chillon-Marinas C, Snethlage CE, Singhal SM, McAlonis-Downes M et al. 2021. Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB. Nat. Neurosci. 24:1089–99
    [Google Scholar]
  29. Makeyev EV, Zhang J, Carrasco MA, Maniatis T. 2007. The microRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol. Cell 27:435–48
    [Google Scholar]
  30. Markovtsov V, Nikolic JM, Goldman JA, Turck CW, Chou MY, Black DL. 2000. Cooperative assembly of an hnRNP complex induced by a tissue-specific homolog of polypyrimidine tract binding protein. Mol. Cell. Biol. 20:7463–79
    [Google Scholar]
  31. Mathiesen SN, Lock JL, Schoderboeck L, Abraham WC, Hughes SM. 2020. CNS transduction benefits of AAV-PHP.eB over AAV9 are dependent on administration route and mouse strain. Mol. Ther. Methods Clin. Dev. 19:447–58
    [Google Scholar]
  32. Niu W, Zang T, Smith DK, Vue TY, Zou Y et al. 2015. SOX2 reprograms resident astrocytes into neural progenitors in the adult brain. Stem Cell Rep. 4:780–94
    [Google Scholar]
  33. Niu W, Zang T, Wang L-L, Zou Y, Zhang C-L. 2018. Phenotypic reprogramming of striatal neurons into dopaminergic neuron-like cells in the adult mouse brain. Stem Cell Rep. 11:1156–70
    [Google Scholar]
  34. Niu W, Zang T, Zou Y, Fang S, Smith DK et al. 2013. In vivo reprogramming of astrocytes to neuroblasts in the adult brain. Nat. Cell Biol. 15:1164–75
    [Google Scholar]
  35. Patton JG, Mayer SA, Tempst P, Nadal-Ginard B. 1991. Characterization and molecular cloning of polypyrimidine tract-binding protein: a component of a complex necessary for pre-mRNA splicing. Genes Dev. 5:1237–51
    [Google Scholar]
  36. Pilz GA, Bottes S, Betizeau M, Jörg DJ, Carta S et al. 2018. Live imaging of neurogenesis in the adult mouse hippocampus. Science 359:658–62
    [Google Scholar]
  37. Qian H, Kang X, Hu J, Zhang D, Liang Z et al. 2020. Reversing a model of Parkinson's disease with in situ converted nigral neurons. Nature 582:550–56
    [Google Scholar]
  38. Shibasaki T, Tokunaga A, Sakamoto R, Sagara H, Noguchi S et al. 2013. PTB deficiency causes the loss of adherens junctions in the dorsal telencephalon and leads to lethal hydrocephalus. Cereb. Cortex 23:1824–35
    [Google Scholar]
  39. Shibayama M, Ohno S, Osaka T, Sakamoto R, Tokunaga A et al. 2009. Polypyrimidine tract-binding protein is essential for early mouse development and embryonic stem cell proliferation. FEBS J. 276:6658–68
    [Google Scholar]
  40. Smith DK, Wang L, Zhang CL. 2016. Physiological, pathological, and engineered cell identity reprogramming in the central nervous system. Wiley Interdiscip. Rev. Dev. Biol. 5:499–517
    [Google Scholar]
  41. Su Z, Niu W, Liu ML, Zou Y, Zhang CL. 2014. In vivo conversion of astrocytes to neurons in the injured adult spinal cord. Nat. Commun. 5:3338
    [Google Scholar]
  42. Svendsen CN, Sofroniew MV. 2022. Lineage tracing: the gold standard to claim direct reprogramming in vivo. Mol. Ther. 30:988–89
    [Google Scholar]
  43. Tai W, Wu W, Wang LL, Ni H, Chen C et al. 2021. In vivo reprogramming of NG2 glia enables adult neurogenesis and functional recovery following spinal cord injury. Cell Stem Cell 28:923–37.e4
    [Google Scholar]
  44. Tai W, Xu XM, Zhang CL. 2020. Regeneration through in vivo cell fate reprogramming for neural repair. Front. Cell Neurosci. 14:107
    [Google Scholar]
  45. Todd L, Hooper MJ, Haugan AK, Finkbeiner C, Jorstad N et al. 2021. Efficient stimulation of retinal regeneration from Müller glia in adult mice using combinations of proneural bHLH transcription factors. Cell Rep. 37:109857
    [Google Scholar]
  46. Torper O, Pfisterer U, Wolf DA, Pereira M, Lau S et al. 2013. Generation of induced neurons via direct conversion in vivo. PNAS 110:7038–43
    [Google Scholar]
  47. Wang LL, Serrano C, Zhong X, Ma S, Zou Y, Zhang CL. 2021. Revisiting astrocyte to neuron conversion with lineage tracing in vivo. Cell 184:5465–81.e16
    [Google Scholar]
  48. Wang LL, Su Z, Tai W, Zou Y, Xu XM, Zhang CL. 2016. The p53 pathway controls SOX2-mediated reprogramming in the adult mouse spinal cord. Cell Rep. 17:891–903
    [Google Scholar]
  49. Wang LL, Zhang CL. 2018. Engineering new neurons: in vivo reprogramming in mammalian brain and spinal cord. Cell Tissue Res. 371:201–12
    [Google Scholar]
  50. Wang LL, Zhang CL. 2022a. In vivo glia-to-neuron conversion: pitfalls and solutions. Dev. Neurobiol. 82:367–74
    [Google Scholar]
  51. Wang LL, Zhang CL. 2022b. Reply to In vivo confusion over in vivo conversion. Mol. Ther. 30:986–87
    [Google Scholar]
  52. Xie Y, Zhou J, Chen B 2022. Critical examination of Ptbp1-mediated glia-to-neuron conversion in the mouse retina. Cell Rep. 39:110960
    [Google Scholar]
  53. Xue Y, Ouyang K, Huang J, Zhou Y, Ouyang H et al. 2013. Direct conversion of fibroblasts to neurons by reprogramming PTB-regulated microRNA circuits. Cell 152:82–96
    [Google Scholar]
  54. Yang RY, Chai R, Pan JY, Bao JY, Xia PH et al. 2023. Knockdown of polypyrimidine tract binding protein facilitates motor function recovery after spinal cord injury. Neural Regen. Res. 18:396–403
    [Google Scholar]
  55. Yao K, Qiu S, Wang YV, Park SJH, Mohns EJ et al. 2018. Restoration of vision after de novo genesis of rod photoreceptors in mammalian retinas. Nature 560:484–88
    [Google Scholar]
  56. Zhang Y, Li B, Cananzi S, Han C, Wang LL et al. 2022. A single factor elicits multilineage reprogramming of astrocytes in the adult mouse striatum. PNAS 119:e2107339119
    [Google Scholar]
  57. Zhou H, Su J, Hu X, Zhou C, Li H et al. 2020. Glia-to-neuron conversion by CRISPR-CasRx alleviates symptoms of neurological disease in mice. Cell 181:590–603.e16
    [Google Scholar]
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