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The microRNA, miR-18a, regulates NeuroD and photoreceptor differentiation in the retina of the zebrafish

View ORCID ProfileScott M. Taylor, Emily Giuffre, Patience Moseley, Peter F. Hitchcock
doi: https://doi.org/10.1101/440263
Scott M. Taylor
aDepartment of Biology, University of West Florida, 11000 University Parkway, Pensacola, FL32514
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Emily Giuffre
aDepartment of Biology, University of West Florida, 11000 University Parkway, Pensacola, FL32514
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Patience Moseley
aDepartment of Biology, University of West Florida, 11000 University Parkway, Pensacola, FL32514
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Peter F. Hitchcock
bOphthalmology and Visual Sciences, University of Michigan, W. K. Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105
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ABSTRACT

During embryonic retinal development, six types of retinal neurons are generated from a pool of multipotent progenitors in a strict spatiotemporal pattern. This pattern requires cell cycle exit (i.e. neurogenesis) and differentiation to be precisely regulated in a lineage-specific manner. In zebrafish, the bHLH transcription factor NeuroD governs photoreceptor genesis through Notch signaling but also governs photoreceptor differentiation though distinct mechanisms that are currently unknown. Also unknown are the mechanisms that regulate NeuroD and the spatiotemporal pattern of photoreceptor development. Members of the miR-17-92 microRNA cluster regulate CNS neurogenesis, and a member of this cluster, miR-18a, is predicted to target neuroD mRNA. The purpose of this study was to determine if miR-18a regulates NeuroD in the retina and if it plays a role in photoreceptor development. Quantitative RT-PCR showed that, of the three miR-18 family members (miR-18a, b and c), miR-18a expression most closely parallels neuroD expression. Morpholino oligonucleotides and CRISPR/Cas9 gene editing were used for miR-18a loss-of-function (LOF) and both approaches resulted in larvae with more mature photoreceptors at 70 hpf without affecting cell proliferation. Western blot showed that miR-18a LOF increases NeuroD protein levels and in vitro dual luciferase assay showed that miR-18a directly interacts with the 32UTR of neuroD. Finally, tgif1 mutants have increased miR-18a expression, less NeuroD protein and fewer mature photoreceptors, and the photoreceptor deficiency is rescued by miR-18a knockdown. Together these results show that, independent of neurogenesis, miR-18a regulates the timing of photoreceptor differentiation and indicate that this occurs through post-transcriptional regulation of NeuroD.

ACKNOWLEDGEMENTS

This work was supported by grants from the National Institutes of Health (NEI)-R01EY07060 (PFH), T32EY013934 (SMT), P30EY07003 (PFH) and an unrestricted grant from the Research to Prevent Blindness, New York. The authors declare no competing financial interests. The authors thank Laura Kakuk-Atkins and Dilip Pawar for technical assistance. Fish lines and reagents provided by ZIRC were supported by NIH-NCRR Grant P40 RR01.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 10, 2018.
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The microRNA, miR-18a, regulates NeuroD and photoreceptor differentiation in the retina of the zebrafish
Scott M. Taylor, Emily Giuffre, Patience Moseley, Peter F. Hitchcock
bioRxiv 440263; doi: https://doi.org/10.1101/440263
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The microRNA, miR-18a, regulates NeuroD and photoreceptor differentiation in the retina of the zebrafish
Scott M. Taylor, Emily Giuffre, Patience Moseley, Peter F. Hitchcock
bioRxiv 440263; doi: https://doi.org/10.1101/440263

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