Diversification of multipotential postmitotic mouse retinal ganglion cell precursors into discrete types

  1. Karthik Shekhar  Is a corresponding author
  2. Irene E Whitney
  3. Salwan Butrus
  4. Yi-Rong Peng
  5. Joshua R Sanes  Is a corresponding author
  1. University of California, Berkeley, United States
  2. Harvard University, United States
  3. University of California, Los Angeles, United States

Abstract

The genesis of broad neuronal classes from multipotential neural progenitor cells has been extensively studied, but less is known about the diversification of a single neuronal class into multiple types. We used single-cell RNA-seq to study how newly-born (postmitotic) mouse retinal ganglion cell (RGC) precursors diversify into ~45 discrete types. Computational analysis provides evidence that RGC transcriptomic type identity is not specified at mitotic exit, but acquired by gradual, asynchronous restriction of postmitotic multipotential precursors. Some types are not identifiable until a week after they are generated. Immature RGCs may be specified to project ipsilaterally or contralaterally to the rest of the brain before their type identity emerges. Optimal transport inference identifies groups of RGC precursors with largely non-overlapping fates, distinguished by selectively expressed transcription factors that could act as fate determinants. Our study provides a framework for investigating the molecular diversification of discrete types within a neuronal class.

Data availability

Sequencing data has been submitted under GSE185671. Reviewer token : evchicgutpqpnoj.Computational scripts are available at : https://github.com/shekharlab/mouseRGCdev

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Karthik Shekhar

    Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, United States
    For correspondence
    kshekhar@berkeley.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4349-6600
  2. Irene E Whitney

    Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States
    Competing interests
    Irene E Whitney, is affiliated with Honeycomb Biotechnologies. The author has no financial interests to declare..
  3. Salwan Butrus

    Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  4. Yi-Rong Peng

    Department of Ophthalmology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  5. Joshua R Sanes

    Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States
    For correspondence
    sanesj@mcb.harvard.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8926-8836

Funding

National Institutes of Health (R37NS029169)

  • Joshua R Sanes

National Institutes of Health (R01EY022073)

  • Joshua R Sanes

National Institutes of Health (R00EY028625)

  • Karthik Shekhar

National Science Foundation (GRP DGE1752814)

  • Salwan Butrus

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were approved by the Institutional Animal Care and Use Committees (IACUC) at Harvard University. Mice were maintained in pathogen-free facilities under standard housing conditions with continuous access to food and water. Animals used in this study include both males and females. A meta-analysis (not shown) did not show any systematic sex-related effects in either differentially expressed genes or cell-type proportions.

Reviewing Editor

  1. Carol A Mason, Columbia University, United States

Publication history

  1. Received: September 11, 2021
  2. Preprint posted: October 21, 2021 (view preprint)
  3. Accepted: February 21, 2022
  4. Accepted Manuscript published: February 22, 2022 (version 1)
  5. Version of Record published: March 25, 2022 (version 2)

Copyright

© 2022, Shekhar et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Karthik Shekhar
  2. Irene E Whitney
  3. Salwan Butrus
  4. Yi-Rong Peng
  5. Joshua R Sanes
(2022)
Diversification of multipotential postmitotic mouse retinal ganglion cell precursors into discrete types
eLife 11:e73809.
https://doi.org/10.7554/eLife.73809

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