@article{fa0071e027e94276ba3a71c8fc0a506f,
title = "Notch-mediated re-specification of neuronal identity during central nervous system development",
abstract = "Neuronal identity has long been thought of as immutable, so that once a cell acquires a specific fate, it is maintained for life.1 Studies using the overexpression of potent transcription factors to experimentally reprogram neuronal fate in the mouse neocortex2,3 and retina4,5 have challenged this notion by revealing that post-mitotic neurons can switch their identity. Whether fate reprogramming is part of normal development in the central nervous system (CNS) is unclear. While there are some reports of physiological cell fate reprogramming in invertebrates,6,7 and in the vertebrate peripheral nervous system,8 endogenous fate reprogramming in the vertebrate CNS has not been documented. Here, we demonstrate spontaneous fate re-specification in an interneuron lineage in the zebrafish retina. We show that the visual system homeobox 1 (vsx1)-expressing lineage, which has been associated exclusively with excitatory bipolar cell (BC) interneurons,9–12 also generates inhibitory amacrine cells (ACs). We identify a role for Notch signaling in conferring plasticity to nascent vsx1 BCs, allowing suitable transcription factor programs to re-specify them to an AC fate. Overstimulating Notch signaling enhances this physiological phenotype so that both daughters of a vsx1 progenitor differentiate into ACs and partially differentiated vsx1 BCs can be converted into ACs. Furthermore, this physiological re-specification can be mimicked to allow experimental induction of an entirely distinct fate, that of retinal projection neurons, from the vsx1 lineage. Our observations reveal unanticipated plasticity of cell fate during retinal development.",
keywords = "CNS, asymmetric division, cell fate, development, interneuron, neurogenesis, notch, reprogramming, retina, zebrafish",
author = "Peter Engerer and Eleni Petridou and Williams, {Philip R.} and Suzuki, {Sachihiro C.} and Takeshi Yoshimatsu and Ruben Portugues and Thomas Misgeld and Leanne Godinho",
note = "Funding Information: We thank K. Wullimann for fish husbandry, Y. Hufnagel for technical support, M. Schetterer for administrative support, and S. Vagionitis for critical reading of an earlier version of this manuscript. We are grateful to M. Nonet (Washington University in St. Louis), M. Meyer (King{\textquoteright}s College London), and J. Clarke (King{\textquoteright}s College London) for the pCold Heart Tol2 vector, 5xUAS:TagRFP-T, and PCS2 Numb-GFP vectors, respectively. We thank S. Higashijima (National Institutes of Natural Sciences, Okazaki Institute for Integrative Bioscience) for the Tg(vsx1:GFP)nns5 and Tg(vsx2:GFP)nns1 BAC transgenic lines. We are very grateful to Rachel Wong (University of Washington, Seattle), who generously supported this project and provided the following transgenic lines: Tg(14xUAS:MYFP) and Tg(crx:MA-CFP)q20. We thank L. Lagnado (University of Sussex, UK) for the Tg(−1.8ctbp2:gap43-EGFP)lmb1 line. This project was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through SFB870, TP A11, reference number 118803580 . Work in L.G.{\textquoteright}s and R.P.{\textquoteright}s groups is further supported by the DFG through TRR-274, TP C04, Project ID 408885537 . T.M. and R.P. are supported by the Munich Center for Systems Neurology (SyNergy; EXC 2145 ). T.M. is further supported by the German Center for Neurodegenerative Diseases (DZNE Munich). P.E. was supported by the DFG Research Training Group 1373 and the Graduate School of the Technische Universit{\"a}t M{\"u}nchen (TUM-GS). E.P. is supported by the Elite Network of Bavaria (MSc “Biomedical Neuroscience”). P.R.W. was supported by the Human Frontier Science Program and the Wings for Life Foundation . S.C.S. and T.Y. were supported by a grant awarded to R. Wong ( NIH EY14358 ). Funding Information: We thank K. Wullimann for fish husbandry, Y. Hufnagel for technical support, M. Schetterer for administrative support, and S. Vagionitis for critical reading of an earlier version of this manuscript. We are grateful to M. Nonet (Washington University in St. Louis), M. Meyer (King's College London), and J. Clarke (King's College London) for the pCold Heart Tol2 vector, 5xUAS:TagRFP-T, and PCS2 Numb-GFP vectors, respectively. We thank S. Higashijima (National Institutes of Natural Sciences, Okazaki Institute for Integrative Bioscience) for the Tg(vsx1:GFP)nns5 and Tg(vsx2:GFP)nns1 BAC transgenic lines. We are very grateful to Rachel Wong (University of Washington, Seattle), who generously supported this project and provided the following transgenic lines: Tg(14xUAS:MYFP) and Tg(crx:MA-CFP)q20. We thank L. Lagnado (University of Sussex, UK) for the Tg(?1.8ctbp2:gap43-EGFP)lmb1 line. This project was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through SFB870, TP A11, reference number 118803580. Work in L.G.?s and R.P.?s groups is further supported by the DFG through TRR-274, TP C04, Project ID 408885537. T.M. and R.P. are supported by the Munich Center for Systems Neurology (SyNergy; EXC 2145). T.M. is further supported by the German Center for Neurodegenerative Diseases (DZNE Munich). P.E. was supported by the DFG Research Training Group 1373 and the Graduate School of the Technische Universit?t M?nchen (TUM-GS). E.P. is supported by the Elite Network of Bavaria (MSc ?Biomedical Neuroscience?). P.R.W. was supported by the Human Frontier Science Program and the Wings for Life Foundation. S.C.S. and T.Y. were supported by a grant awarded to R. Wong (NIH EY14358). P.E. E.P. P.R.W. T.M. and L.G. conceived of the project and designed the experiments. L.G. and T.M. supervised the project. P.E. and E.P. performed the experiments. P.E. S.C.S. T.Y. and L.G. generated new constructs and transgenic lines. R.P. advised on the data analysis. L.G. wrote the paper, with input from all of the authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = nov,
day = "8",
doi = "10.1016/j.cub.2021.08.049",
language = "English",
volume = "31",
pages = "4870--4878.e5",
journal = "Current Biology",
issn = "0960-9822",
number = "21",
}