Notch suppression collaborates with Ascl1 and Lin28 to unleash a regenerative response in fish retina, but not in mice
- Fairouz Elsaeidi1,
- Peter Macpherson1,
- Elizabeth A. Mills1,
- Jonathan Jui2,
- John G. Flannery2, and
- Daniel Goldman1
- 1Molecular and Behavioral Neuroscience Institute, Department of Biological Chemistry, University of Michigan, Ann Arbor MI 48109, USA.
- 2Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA.
- Correspondence: Daniel Goldman, 5045 BSRB, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109. Email: neuroman{at}umich.edu
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Author contributions: DG designed research and wrote paper; FE, PM, and EM performed research; DG, FE, PM, and EM analyzed data; JJ and JGF contributed reagents.
Abstract
Muller glial cells (MG) in the zebrafish retina respond to injury by acquiring retinal stem cell characteristics. Thousands of gene expression changes are associated with this event. Key among these changes are the induction of Ascl1a and Lin28a, two reprogramming factors whose expression is necessary for retina regeneration. Whether these factors are sufficient to drive MG proliferation and subsequent neuronal-fate specification remains unknown. To test this, we conditionally expressed Ascl1a and Lin28a in the uninjured retina of male and female fish. We found that together, their forced expression only stimulates sparse MG proliferation. However, in combination with Notch signaling inhibition, widespread MG proliferation and neuron regeneration ensued. Remarkably, Ascl1 and Lin28a expression in the retina of male and female mice also stimulated sparse MG proliferation, although this was not enhanced when combined with inhibitors of Notch signaling. Lineage tracing in both fish and mice suggested that the proliferating MG generated multipotent progenitors; however, this process was much more efficient in fish than mice. Overall, our studies suggest that the overexpression of Ascl1a and Lin28a in zebrafish, in combination with inhibition of Notch signaling, can phenocopy the effects of retinal injury in Muller glia. Interestingly, Ascl1 and Lin28a seem to have similar effects in fish and mice, while Notch signaling may differ. Understanding the different consequences of Notch signaling inhibition in fish and mice, may suggest additional strategies for enhancing retina regeneration in mammals.
SIGNIFICANCE STATEMENT
Mechanisms underlying retina regeneration in fish may suggest strategies for stimulating this process in mammals. Here we report that forced expression of Ascl1 and Lin28a can stimulate sparse MG proliferation in fish and mice; however, only in fish does Notch signaling inhibition collaborate with Ascl1a and Lin28a to stimulate widespread MG proliferation in the uninjured retina. Discerning differences in Notch signaling between fish and mice MG may reveal strategies for stimulating retina regeneration in mammals.
Footnotes
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The authors declare no competing financial interests.
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This work was supported by grants from the NIH (NEI RO1 EY018132 and NEI RO1 EY027310 to DG, NEI R01 EY022975 to JGF, and Kirschstein NRSA T32HD007505-20 to EAM); a Research to Prevent Blindness Innovative Ophthalmic Research Award and gifts from the Marjorie and Maxwell Jospey Foundation and the Shirlye and Peter Helman Fund to DG; and the Foundation Fighting Blindness and the Lowy Medical Research Institute to JGF. We thank Curtis Powell for generating hsp70:ascl1a and hsp70:lin28a transgenic zebrafish. Curtis Powell and Rahaman Gangji for preliminary characterization of hsp70:ascl1a and hsp70:lin28a transgenic lines. Michael Parsons (Johns Hopkins University) for tp1:mCherry transgenic fish; Ivan Maillard (UM) for providing DN-MAML mice; and Joshua Kirk for maintaining our zebrafish colony.
- Received July 27, 2017.
- Revision received January 15, 2018.
- Accepted January 19, 2018.
- Copyright © 2018 the authors
