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Evidence of Müller Glia Conversion Into Retina Ganglion Cells Using bioRxiv preprint doi: https://doi.org/10.1101/399717; this version posted August 24, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Evidence of Müller glia conversion into retina ganglion cells using 2 Neurogenin2 3 4 Roberta Pereira de Melo Guimarães1,3,4,&, Bruna Soares Landeira1,&, Diego 5 Marques Coelho1,2, Daiane Cristina Ferreira Golbert1, Mariana S. Silveira3, 6 Rafael Linden3, Ricardo A. de Melo Reis4 and Marcos R. Costa1,* 7 1Brain Institute, Federal University of Rio Grande do Norte, Natal, 59056-450, Brazil 8 2Bioinformatics Multidisciplinary Environment, IMD, Federal University of Rio Grande do 9 Norte, Brazil 10 3Lab Neurogenesis, 4Lab Neurochemistry, Institute of Biophysics Carlos Chagas Filho, 11 UFRJ, Rio de Janeiro, Brazil 12 &These authors have equally contributed to the work 13 14 Corresponding author: 15 [email protected] 16 Av. Nascimento de Castro 2155, Lagoa Nova 17 Natal, 59056-450 RN, Brazil 18 19 Running title: Conversion of retina MGCs into ganglion cells 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 bioRxiv preprint doi: https://doi.org/10.1101/399717; this version posted August 24, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 38 Abstract 39 Macular Degeneration, Glaucoma, and Retinitis Pigmentosa are all leading causes of 40 irreversible visual impairment in the elderly, affecting hundreds of millions of patients. 41 Müller glia cells (MGC), the main type of glia found in the vertebrate retina, can resume 42 proliferation in the adult injured retina and contribute to tissue repair. Also, MGC can be 43 genetically reprogrammed through the expression of the transcription factor (TF) 44 Achaete-scute homolog 1 (ASCL1) into induced neurons (iNs), displaying key hallmarks 45 of photoreceptors, bipolar and amacrine cells, which may contribute to regenerate the 46 damaged retina. Here, we show that the TF neurogenin 2 (NEUROG2) is also sufficient 47 to lineage-reprogram MGC into iNs. The efficiency of MGC lineage conversion by 48 NEUROG2 is similar to that observed after expression of ASCL1. However, 49 reprogramming efficiency is affected by previous exposure to EGF and FGF2 during the 50 expansion of MGC population. Transduction of either Neurog2 or Ascl1 led to the 51 upregulation of key retina neuronal genes in MGC-derived iNs, but only NEUROG2 52 induced a consistent increase in the expression of putative retinal ganglion cell (RGC) 53 genes. In vivo electroporation of Neurog2 in the neonatal retina also induced a shift in 54 the generation of retinal cell subtypes, favoring the differentiation RGCs at the expense 55 of MGCs. Altogether, our data indicate that Neurog2 induces lineage conversion of 56 MGCs into RGC-like iNs. 57 58 Keywords: Retina; Müller glia cells; Induced neurons; Lineage-reprogramming; 59 Neurogenin2; Ascl1 60 61 62 63 bioRxiv preprint doi: https://doi.org/10.1101/399717; this version posted August 24, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 64 Introduction 65 The retina is a unique tissue with highly organized architecture, known to be one 66 of the most energetically demanding systems in the nervous system (Wong-Riley, 67 2010). Due to oxidative stress, trauma or genetic mutations, gradual and irreversible cell 68 death affects specific neuronal types in the retina (Athanasiou et al., 2013). Several 69 neurodegenerative diseases affect the visual system and may lead to incurable 70 blindness, such as retinitis pigmentosa, age-related macular degeneration and 71 glaucoma (Bramall et al., 2010;Zhang et al., 2016). For instance, retinal ganglion cells 72 (RGCs) degenerate in glaucoma eventually leading to blindness. In the last five years 73 almost 65 million people worldwide were diagnosed with glaucoma (Gill et al., 74 2016;Liang et al., 2017), which is the leading cause of visual impairment in developed 75 countries (WHO). Still, despite the social and economic burden of such diseases, 76 therapeutic approaches are limited. Recent progress in cell-based therapy may, 77 nonetheless, provide novel means to restore vision in glaucoma patients (Abu-Hassan 78 et al., 2015;Chamling et al., 2016). 79 Cell lineage-reprogramming techniques, which allow the direct conversion of a 80 non-neuronal cell into neurons, offer a powerful strategy to regenerate neuronal cells in 81 the injured retina. In fact, expression of the bHLH neurogenic transcription factor (TF) 82 Achaete-scute homolog 1 (ASCL1) in vitro induced the reprogramming of mouse Müller 83 glia cells (MGC) into bipolar cells and, to a lesser extent, amacrine cells (Pollak et al., 84 2013). Following NMDA-mediated injury in postnatal mouse retina, ASCL1 expression 85 reprogrammed MGCs into neurons expressing markers of bipolar cells, amacrine cells 86 and photoreceptors (Ueki et al., 2015). Notably, when combined with the inhibitor of bioRxiv preprint doi: https://doi.org/10.1101/399717; this version posted August 24, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 87 histone deacetylases trichostatin A, expression of ASCL1 elicited the conversion of 88 some MGC into bipolar and amacrine cells in the injured adult retina (Jorstad et al., 89 2017). These findings demonstrate that regenerative effects of transgenic expression of 90 ASCL1 in mouse Müller glia are akin to the regenerative response observed in non- 91 mammalian vertebrates (Wilken and Reh, 2016). However, ASCL1 expression is not 92 sufficient to reprogram MGCs into RGCs either in vitro or in vivo (9-11). 93 During development, expression of ASCL1 defines a subset of retinal progenitor 94 cells (RPCs) that generate all neuronal types in the retina, except RGCs (Brzezinski et 95 al., 2011). In contrast, expression of the bHLH TF Neurogenin 2 (NEUROG2) defines a 96 separate set of RPCs, co-expressing the POU Class 4 Homeobox 1 and 2 97 (Pou4f1/Brn3a and Pou4f2/Brn3b) and contributing to the generation of RGCs 98 (Hufnagel et al., 2010;Brzezinski et al., 2011). Interestingly, knocking down the 99 expression of Pou4f2/Brn3b in MGCs cultured in conditions to induce stem cell-like 100 properties hampers the differentiation into RGCs (Singhal et al., 2012;Song et al., 101 2013;Wu et al., 2016). 102 Here we report that forced expression of NEUROG2 is sufficient to convert MGC 103 into a neurogenic state. Either ASCL1 or NEUROG2 elicited induced neurons (iNs) that 104 express genes of bipolar, horizontal and amacrine cells, as well as photoreceptors. 105 However, only forced expression of NEUROG2 led to the generation of iNs expressing 106 hallmarks of RGCs. We also show that treatment with epidermal growth factor (EGF) 107 and basic fibroblast growth factor (FGF-2) during the expansion of MGCs affects 108 lineage-conversion efficiencies and iN-fate specification. Finally, we provide evidence 109 for an instructive role of NEUROG2 in the specification of RGC fate in vivo. Collectively, bioRxiv preprint doi: https://doi.org/10.1101/399717; this version posted August 24, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 110 our results may contribute to design new strategies to reprogram MGC into RGCs in the 111 adult mammalian retina and, therefore, to the advance of gene-based therapies to treat 112 retinal degenerations. 113 114 Materials and Methods 115 Animals 116 C57BL/6 mice were obtained from the Biotério Setorial do Instituto do Cérebro 117 (BISIC). All experiments were approved by and carried out in accordance with the 118 guidelines of the Institutional Animal Care and Use Committee of the Federal University 119 of Rio Grande do Norte (license number #048/2014). 120 121 Müller glial cell (MGC) culture 122 MGCs were purified from postnatal day (P)7-9 mice according to previously 123 described protocols (de Melo Reis et al., 2008). Briefly, retinas were dissected out and 124 chemically dissociated with TrypLE (Life Technologies) for 10 min at 37ºC. Isolated 125 cells were counted using a Neubeuer chamber and plated onto T75 culture flasks with 126 DMEM F12 (Gibco) plus 10% fetal bovine serum (Gibco), 3.5 mM glucose (Sigma), 127 4.5g/L GlutaMax (Gibco), 100U/mL penicillin/streptomycin (Gibco), either with or without 128 10 ng/mL of epidermal growth factor (EGF, Gibco) and 10 ng/mL of fibroblast growth 129 factor 2 (FGF2, Gibco). Half of the medium was changed once a week during the period 130 of MGCs expansion. 131 132 Plasmids bioRxiv preprint doi: https://doi.org/10.1101/399717; this version posted August 24, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 133 Plasmids contain the internal chicken β-actin promoter fused with a 134 cytomegalovirus enhancer (pCAG), the coding sequence for either Ascl1 or Neurog2, 135 an internal ribosomal entry site (I) and coding sequences for either DsRed or GFP 136 (pCAG-Ascl1-I-DsRed, pCAG-Neurog2-I-DsRed and pCAG-Neurog2-I-GFP).
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