Transcriptome analysis of the zebrafish<i>atoh7−/−</i>Mutant,<i>lakritz</i>, highlights Atoh7‐dependent genetic networks with potential implications for human eye diseases

Covello, Giuseppina; Rossello, Fernando; Filosi, Michele; Gajardo, Felipe; Duchemin, Anne-Laure; Tremonti, Beatrice F.; Eichenlaub, Michael P.; Polo, José M.; Powell, David R.; Ngai, John; Allende, Miguel L.; Domenici, Enrico; Ramialison, Mirana; Poggi, Lucia

doi:10.1096/fba.2020-00030

Cited by 4 publications

(5 citation statements)

References 140 publications

(181 reference statements)

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“…We took advantage of lak mutant larvae that lack RGCs to address whether this role for the eye is conserved in the diurnal zebrafish. Homozygous lak mutant larvae lack neuronal connections between the eye and the brain and do not display an optomotor response [ 32 , 36 , 37 ]. The gene mutated in lak , encoding for the bHLH transcription factor ATOH7 (ATH5) is expressed exclusively in the developing retina [ 38 ].…”

Section: Resultsmentioning

confidence: 99%

Contribution of the eye and of opn4xa function to circadian photoentrainment in the diurnal zebrafish

Chaigne,

Sapède,

Cousin

et al. 2024

PLoS Genet

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The eye is instrumental for controlling circadian rhythms in mice and human. Here, we address the conservation of this function in the zebrafish, a diurnal vertebrate. Using lakritz (lak) mutant larvae, which lack retinal ganglion cells (RGCs), we show that while a functional eye contributes to masking, it is largely dispensable for the establishment of circadian rhythms of locomotor activity. Furthermore, the eye is dispensable for the induction of a phase delay following a pulse of white light at CT 16 but contributes to the induction of a phase advance upon a pulse of white light at CT21. Melanopsin photopigments are important mediators of photoentrainment, as shown in nocturnal mammals. One of the zebrafish melanopsin genes, opn4xa, is expressed in RGCs but also in photosensitive projection neurons in the pineal gland. Pineal opn4xa+ projection neurons function in a LIGHT ON manner in contrast to other projection neurons which function in a LIGHT OFF mode. We generated an opn4xa mutant in which the pineal LIGHT ON response is impaired. This mutation has no effect on masking and circadian rhythms of locomotor activity, or for the induction of phase shifts, but slightly modifies period length when larvae are subjected to constant light. Finally, analysis of opn4xa;lak double mutant larvae did not reveal redundancy between the function of the eye and opn4xa in the pineal for the control of phase shifts after light pulses. Our results support the idea that the eye is not the sole mediator of light influences on circadian rhythms of locomotor activity and highlight differences in the circadian system and photoentrainment of behaviour between different animal models.

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Section: Resultsmentioning

confidence: 99%

Contribution of the eye and of opn4xa function to circadian photoentrainment in the diurnal zebrafish

Chaigne,

Sapède,

Cousin

et al. 2024

PLoS Genet

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“…We took advantage of lak mutant larvae that lack RGCs to address whether this role for the eye is conserved in the diurnal zebrafish. Homozygous lak mutant larvae lack neuronal connections between the eye and the brain and do not display an optomotor response (Covello et al, 2020; Kay et al, 2001; Neuhauss et al, 1999). In cycles of 14h light:10h dark (hereafter referred to as LD), both control and lak mutant larvae exhibit rhythms of locomotor activity that are aligned with the LD cycles (Fig 1B).…”

Section: Resultsmentioning

confidence: 99%

“…We took advantage of lak mutant larvae that lack RGCs to address whether this role for the eye is conserved in the diurnal zebrafish. Homozygous lak mutant larvae lack neuronal connections between the eye and the brain and do not display an optomotor response (Covello et al, 2020; Kay et al, 2001; Neuhauss et al, 1999). We compared the locomotor activity of homozygous lak mutants with siblings ( lak +/+ and lak +/-) in different illumination conditions.…”

Section: Resultsmentioning

confidence: 99%

“…We took advantage of lak mutant larvae that lack RGCs to address whether this role for the eye is conserved in the diurnal zebrafish. Homozygous lak mutant larvae lack neuronal connections between the eye and the brain and do not display an optomotor response (Covello et al, 2020; Kay et al, 2001; Neuhauss et al, 1999). The gene mutated in lak , encoding for the bHLH transcription factor ATOH7 (ATH5) is expressed in the developing retina and nowhere else (Masai et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

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Contribution of the eye and ofopn4xafunction to circadian photoentrainment in the diurnal zebrafish

Cau

Chaigne

Cousin

et al. 2022

Preprint

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The eye is instrumental for controlling circadian rhythms in nocturnal mammals. Here, we address the conservation of this function in the zebrafish, a diurnal vertebrate. Using lakritz (lak) mutant larvae, which lack retinal ganglion cells (RGCs), we show that while a functional eye is required for a phenomenon known as masking, it is largely dispensable for the establishment of circadian rhythms of locomotor activity. Furthermore, the eye is dispensable for the induction of a phase delay following a pulse of white light at CT 16 but contributes to the induction of a phase advance upon a pulse of white light at CT21. Melanopsin photopigments are important mediators of photoentrainment in nocturnal mammals. One of the zebrafish melanopsin genes, opn4xa, is expressed in RGCs but also in photosensitive projection neurons in the pineal gland. To address the role of this photopigment, we generated an opn4xa mutant. Abrogating opn4xa has no effect on masking and circadian rhythms of locomotor activity, or for the induction of phase shifts, but is required for period length control when larvae are subjected to constant light. Finally, analysis of opn4xa;lak double mutant larvae did not reveal redundancy between the function of the eye and Opn4xa in the pineal for photoentrainment or phase shifts after light pulses. Our results challenge the dogma that the eye as the sole mediator of light influences on circadian rhythms and highlight profound differences in the circadian system and photoentrainment between different animal models.Significance statementThe eye in general and melanopsin expressing cells in particular are crucial for circadian rhythms in nocturnal mammals, most notably during photoentrainment, by which circadian rhythms adapt to a changing light environment. In marked contrast to this, we show that in the diurnal zebrafish the eye and photosensitivity dependent on the melanopsin gene opn4xa, which expressed in both the eye and the pineal gland, are largely dispensable for correct circadian rhythms. These results provide the first insight that the light sensors orchestrating circadian rhythms are different between animal models raising the intriguing possibility that vertebrates might employ different molecular/cellular circuits for photoentrainment depending on their phylogeny and/or temporal niche.

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“…All affected patients show a similar phenotype that include congenital blindness, nystagmus, glaucoma, corneal opacities, microphthalamus and persistent hyperplastic primary vitreous, caused by a failure of the embryonic vitreous and hyaloid vasculature to regress during development 23,26,60,61 . A recent study compared the transcriptome of atoh7 mutant larvae to a wildtype transcriptome to identify potential genetic networks underlying human eye disease 62 . They identified clusters enriched in retinal development, cell cycle, chromatin remodeling, stress response and Wnt pathway to be differentially expressed in mutants.…”

Section: Atoh7 Mutations Produce Variable Phenotypes In Humansmentioning

confidence: 99%

Blind but alive - congenital loss ofatoh7disrupts the visual system of adult zebrafish

Hammer,

Röppenack,

Yousuf

et al. 2024

Preprint

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Purpose Vision is the predominant sense in most animal species. Loss of vision can be caused by a multitude of factors resulting in anatomical as well as behavioral changes. In mice and zebrafish, atoh7 mutants are completely blind as they fail to generate retinal ganglion cells during development. In contrast to mice, raising blind zebrafish to adulthood is challenging and this important model is currently missing in the field. Here, we report the phenotype of homozygous mutant adult zebrafish atoh7 mutants that have been raised using adjusted feeding and holding conditions. Methods The phenotype of adult mutants was characterized using classical histology and immunohistochemistry as well as optical coherence tomography. In addition, the optokinetic response was characterized. Results Adult atoh7 mutants display dark body pigmentation and significantly reduced body length. They fail to form retinal ganglion cells, the resulting nerve fiber layer as well as the optic nerve, and consequently behave completely blindly. In contrast, increased amounts of other retinal neurons and Muller glia are formed. In addition, the optic tectum is anatomically reduced in size, presumably due to the missing retinal input. Conlusions Taken together, we provide a comprehensive characterization of a completely blind adult zebrafish mutant with focus on retinal and tectal morphology, as a useful model for glaucoma and optic nerve aplasia.

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Transcriptome analysis of the zebrafishatoh7−/−Mutant,lakritz, highlights Atoh7‐dependent genetic networks with potential implications for human eye diseases

Cited by 4 publications

References 140 publications

Contribution of the eye and of opn4xa function to circadian photoentrainment in the diurnal zebrafish

Contribution of the eye and of opn4xa function to circadian photoentrainment in the diurnal zebrafish

Contribution of the eye and ofopn4xafunction to circadian photoentrainment in the diurnal zebrafish

Blind but alive - congenital loss ofatoh7disrupts the visual system of adult zebrafish

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