Her9/Hes4 is required for retinal photoreceptor development, maintenance, and survival

Cagney E. Coomer; Stephen G. Wilson; Kayla F. Titialii-Torres; Jessica D. Bills; Laura A. Krueger; Rebecca A. Petersen; Evelyn M. Turnbaugh; Eden L. Janesch; Ann C. Morris

doi:10.1038/s41598-020-68172-2

Her9/Hes4 is required for retinal photoreceptor development, maintenance, and survival

Cagney E. Coomer, Stephen G. Wilson, Kayla F. Titialii-Torres, Jessica D. Bills, Laura A. Krueger, Rebecca A. Petersen, Evelyn M. Turnbaugh, Eden L. Janesch, Ann C. Morris

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

The intrinsic and extrinsic factors that regulate vertebrate photoreceptor specification and differentiation are complex, and our understanding of all the players is far from complete. Her9, the zebrafish ortholog of human HES4, is a basic helix-loop-helix-orange transcriptional repressor that regulates neurogenesis in several developmental contexts. We have previously shown that her9 is upregulated during chronic rod photoreceptor degeneration and regeneration in adult zebrafish, but little is known about the role of her9 during retinal development. To better understand the function of Her9 in the retina, we generated zebrafish her9 CRISPR mutants. Her9 homozygous mutants displayed striking retinal phenotypes, including decreased numbers of rods and red/green cones, whereas blue and UV cones were relatively unaffected. The reduction in rods and red/green cones correlated with defects in photoreceptor subtype lineage specification. The remaining rods and double cones displayed abnormal outer segments, and elevated levels of apoptosis. In addition to the photoreceptor defects, her9 mutants also possessed a reduced proliferative ciliary marginal zone, and decreased and disorganized Müller glia. Mutation of her9 was larval lethal, with no mutants surviving past 13 days post fertilization. Our results reveal a previously undescribed role for Her9/Hes4 in photoreceptor differentiation, maintenance, and survival.

Original language	English
Article number	11316
Journal	Scientific Reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-68172-2
State	Published - Dec 1 2020

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).

Funding

The authors would like to thank Lucas Vieira Francisco for excellent zebrafish care. We also thank Dr. David Hyde (University of Notre Dame) for generously providing the zebrafish opsin antibodies. This work was supported by a grant from the National Institutes of Health (R01EY021769, to A.C.M.) and the University of Kentucky Lyman T. Johnson graduate fellowship (to C.E.C).

Funders	Funder number
National Institutes of Health (NIH)
National Eye Institute (NEI)	R01EY021769
University of Kentucky

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title = "Her9/Hes4 is required for retinal photoreceptor development, maintenance, and survival",

abstract = "The intrinsic and extrinsic factors that regulate vertebrate photoreceptor specification and differentiation are complex, and our understanding of all the players is far from complete. Her9, the zebrafish ortholog of human HES4, is a basic helix-loop-helix-orange transcriptional repressor that regulates neurogenesis in several developmental contexts. We have previously shown that her9 is upregulated during chronic rod photoreceptor degeneration and regeneration in adult zebrafish, but little is known about the role of her9 during retinal development. To better understand the function of Her9 in the retina, we generated zebrafish her9 CRISPR mutants. Her9 homozygous mutants displayed striking retinal phenotypes, including decreased numbers of rods and red/green cones, whereas blue and UV cones were relatively unaffected. The reduction in rods and red/green cones correlated with defects in photoreceptor subtype lineage specification. The remaining rods and double cones displayed abnormal outer segments, and elevated levels of apoptosis. In addition to the photoreceptor defects, her9 mutants also possessed a reduced proliferative ciliary marginal zone, and decreased and disorganized M{\"u}ller glia. Mutation of her9 was larval lethal, with no mutants surviving past 13 days post fertilization. Our results reveal a previously undescribed role for Her9/Hes4 in photoreceptor differentiation, maintenance, and survival.",

author = "Coomer, {Cagney E.} and Wilson, {Stephen G.} and Titialii-Torres, {Kayla F.} and Bills, {Jessica D.} and Krueger, {Laura A.} and Petersen, {Rebecca A.} and Turnbaugh, {Evelyn M.} and Janesch, {Eden L.} and Morris, {Ann C.}",

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AU - Wilson, Stephen G.

AU - Titialii-Torres, Kayla F.

AU - Bills, Jessica D.

AU - Krueger, Laura A.

AU - Petersen, Rebecca A.

AU - Turnbaugh, Evelyn M.

AU - Janesch, Eden L.

AU - Morris, Ann C.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - The intrinsic and extrinsic factors that regulate vertebrate photoreceptor specification and differentiation are complex, and our understanding of all the players is far from complete. Her9, the zebrafish ortholog of human HES4, is a basic helix-loop-helix-orange transcriptional repressor that regulates neurogenesis in several developmental contexts. We have previously shown that her9 is upregulated during chronic rod photoreceptor degeneration and regeneration in adult zebrafish, but little is known about the role of her9 during retinal development. To better understand the function of Her9 in the retina, we generated zebrafish her9 CRISPR mutants. Her9 homozygous mutants displayed striking retinal phenotypes, including decreased numbers of rods and red/green cones, whereas blue and UV cones were relatively unaffected. The reduction in rods and red/green cones correlated with defects in photoreceptor subtype lineage specification. The remaining rods and double cones displayed abnormal outer segments, and elevated levels of apoptosis. In addition to the photoreceptor defects, her9 mutants also possessed a reduced proliferative ciliary marginal zone, and decreased and disorganized Müller glia. Mutation of her9 was larval lethal, with no mutants surviving past 13 days post fertilization. Our results reveal a previously undescribed role for Her9/Hes4 in photoreceptor differentiation, maintenance, and survival.

AB - The intrinsic and extrinsic factors that regulate vertebrate photoreceptor specification and differentiation are complex, and our understanding of all the players is far from complete. Her9, the zebrafish ortholog of human HES4, is a basic helix-loop-helix-orange transcriptional repressor that regulates neurogenesis in several developmental contexts. We have previously shown that her9 is upregulated during chronic rod photoreceptor degeneration and regeneration in adult zebrafish, but little is known about the role of her9 during retinal development. To better understand the function of Her9 in the retina, we generated zebrafish her9 CRISPR mutants. Her9 homozygous mutants displayed striking retinal phenotypes, including decreased numbers of rods and red/green cones, whereas blue and UV cones were relatively unaffected. The reduction in rods and red/green cones correlated with defects in photoreceptor subtype lineage specification. The remaining rods and double cones displayed abnormal outer segments, and elevated levels of apoptosis. In addition to the photoreceptor defects, her9 mutants also possessed a reduced proliferative ciliary marginal zone, and decreased and disorganized Müller glia. Mutation of her9 was larval lethal, with no mutants surviving past 13 days post fertilization. Our results reveal a previously undescribed role for Her9/Hes4 in photoreceptor differentiation, maintenance, and survival.

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Her9/Hes4 is required for retinal photoreceptor development, maintenance, and survival

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