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 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.

A single-cell guide to retinal development: Cell fate decisions of multipotent retinal progenitors in scRNA-seq

“…However, Hes4 has no ortholog within the mouse genome ( Hu et al, 2019 ; Lu et al, 2020 ; Raj et al, 2020 ; Sridhar et al, 2020 ; Xu et al, 2020 ). In zebrafish, her9 is required for the differentiation, maintenance, and survival of rods and red/green cones ( Coomer et al, 2020 ). Given that mouse retinas contain only 2 cone subtypes (short-wavelength and green cones), additional studies examining the presence and function of HES4 / her9 in retinas of additional cone-dominant species beyond humans and zebrafish will be important for determining the extent to which HES4/her9 expression facilitates expanded color vision.…”

Zebrafish Model in Ophthalmology to Study Disease Mechanism and Drug Discovery

“…Decrease in rod photoreceptors at 5 dpf. Few double cones with short OSs at 12 dpf [121] kif3b Delayed OS development. Rapid rod degeneration by 5 dpf [122] myo7aa…”

Molecular Regulation of Yak Preadipocyte Differentiation and Proliferation by LncFAM200B and ceRNA Regulatory Network Analysis

“…Furthermore, as classical target genes of Notch signaling, the Hairy Enhancer of Split ( HES ) family plays an important role in metabolism [ 23 ]. HES4 can promote the induction of human T-lineage differentiation when Notch signaling occurs at higher levels [ 25 ], and it is involved in regulating the differentiation of photoreceptors in zebrafish [ 26 ]. In the current study, overexpression of lncFAM200B significantly up-regulated the expression levels of NOTCH3 and HES4 during preadipocyte differentiation, and NOTCH3 and HES4 were regulated by miR-148c and miR-6529b, respectively.…”