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Author Notes:

John M. Nickerson, litjn@emory.edu

SF, DS, TG, JHB, and JN were involved in experimental design. SF, DS, TG, MC, NL’H, JS, and VS conducted the experiments and analyzed the data. PI, JMB, JHB, and JN provided the mouse lines and equipment. SF and JN were involved in overall study design. SF, DS, and JN wrote the manuscript. All authors discussed the results and edited the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Research Funding:

This study benefitted from a Challenge Grant from Research to Prevent Blindness, Inc. to the Ophthalmology Department at Emory University, National Institutes of Health (NIH) grants R01EY028450, R01EY021592, R01EY004864, P30EY006360, F31EY028855, R01EY028859, T32EY07092, and T32GMB008490, the Abraham J. and Phyllis Katz Foundation, VA RR&D I01RX002806, I21RX001924, and VA RR&D C9246C (Atlanta Veterans Administration Center for Excellence in Vision and Neurocognitive Rehabilitation). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • retina
  • Lsd1
  • Kdm1a
  • neuroepigenetics
  • retinal degeneration
  • neurodegeneration
  • CELL-FATE DETERMINATION
  • GANGLION-CELLS
  • NEURONAL DIFFERENTIATION
  • CRE RECOMBINASE
  • EXPRESSION
  • GENE
  • TRANSCRIPTION
  • PROGENITOR
  • REPRESSION
  • INHIBITION

Deletion of histone demethylase Lsd1 (Kdm1a) during retinal development leads to defects in retinal function and structure

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Journal Title:

FRONTIERS IN CELLULAR NEUROSCIENCE

Volume:

Volume 17

Publisher:

, Pages 1104592-1104592

Type of Work:

Article | Final Publisher PDF

Abstract:

Purpose: The purpose of this study was to investigate the role of Lysine specific demethylase 1 (Lsd1) in murine retinal development. LSD1 is a histone demethylase that can demethylate mono- and di-methyl groups on H3K4 and H3K9. Using Chx10-Cre and Rho-iCre75 driver lines, we generated novel transgenic mouse lines to delete Lsd1 in most retinal progenitor cells or specifically in rod photoreceptors. We hypothesize that Lsd1 deletion will cause global morphological and functional defects due to its importance in neuronal development. Methods: We tested the retinal function of young adult mice by electroretinogram (ERG) and assessed retinal morphology by in vivo imaging by fundus photography and SD-OCT. Afterward, eyes were enucleated, fixed, and sectioned for subsequent hematoxylin and eosin (H&E) or immunofluorescence staining. Other eyes were plastic fixed and sectioned for electron microscopy. Results: In adult Chx10-Cre Lsd1fl/fl mice, we observed a marked reduction in a-, b-, and c-wave amplitudes in scotopic conditions compared to age-matched control mice. Photopic and flicker ERG waveforms were even more sharply reduced. Modest reductions in total retinal thickness and outer nuclear layer (ONL) thickness were observed in SD-OCT and H&E images. Lastly, electron microscopy revealed significantly shorter inner and outer segments and immunofluorescence showed modest reductions in specific cell type populations. We did not observe any obvious functional or morphological defects in the adult Rho-iCre75 Lsd1fl/fl animals. Conclusion: Lsd1 is necessary for neuronal development in the retina. Adult Chx10-Cre Lsd1fl/fl mice show impaired retinal function and morphology. These effects were fully manifested in young adults (P30), suggesting that Lsd1 affects early retinal development in mice.

Copyright information:

© 2023 Ferdous, Shelton, Getz, Chrenek, L’Hernault, Sellers, Summers, Iuvone, Boss, Boatright and Nickerson.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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