OTX2 and CRX rescue overlapping and photoreceptor‐specific functions in the <i>Drosophila</i> eye

Terrell, David; Xie, Baotong; Workman, Michael J.; Mahato, Simpla; Zelhof, Andrew C.; Gebelein, Brian; Cook, Tiffany

doi:10.1002/dvdy.22782

Cited by 28 publications

(47 citation statements)

References 81 publications

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“…However, target gene expression in R90W retinas was less reduced compared to −/− retinas (Figure 8D, J–M), suggesting CRX [R90W] possessed some residual transcriptional activation activity. In Drosophila, human R90W was able to partially rescue the otd uvi phenotype, consistent with a hypomorphic mechanism [46]. Taken together, our results show that CRX [R90W] is a predominantly hypomorphic mutant CRX protein, representative of substitution mutations associated with mild forms of CRX disease.…”

Section: Discussionsupporting

confidence: 70%

Mechanistically Distinct Mouse Models for CRX-Associated Retinopathy

et al. 2014

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Cone-rod homeobox (CRX) protein is a “paired-like” homeodomain transcription factor that is essential for regulating rod and cone photoreceptor transcription. Mutations in human CRX are associated with the dominant retinopathies Retinitis Pigmentosa (RP), Cone-Rod Dystrophy (CoRD) and Leber Congenital Amaurosis (LCA), with variable severity. Heterozygous Crx Knock-Out (KO) mice (“+/−”) have normal vision as adults and fail to model the dominant human disease. To investigate how different mutant CRX proteins produce distinct disease pathologies, we generated two Crx Knock-IN (K-IN) mouse models: CrxE168d2 (“E168d2”) and CrxR90W (“R90W”). E168d2 mice carry a frameshift mutation in the CRX activation domain, Glu168del2, which is associated with severe dominant CoRD or LCA in humans. R90W mice carry a substitution mutation in the CRX homeodomain, Arg90Trp, which is associated with dominant mild late-onset CoRD and recessive LCA. As seen in human patients, heterozygous E168d2 (“E168d2/+”) but not R90W (“R90W/+”) mice show severely impaired retinal function, while mice homozygous for either mutation are blind and undergo rapid photoreceptor degeneration. E168d2/+ mice also display abnormal rod/cone morphology, greater impairment of CRX target gene expression than R90W/+ or +/− mice, and undergo progressive photoreceptor degeneration. Surprisingly, E168d2/+ mice express more mutant CRX protein than wild-type CRX. E168d2neo/+, a subline of E168d2 with reduced mutant allele expression, displays a much milder retinal phenotype, demonstrating the impact of Crx expression level on disease severity. Both CRX[E168d2] and CRX[R90W] proteins fail to activate transcription in vitro, but CRX[E168d2] interferes more strongly with the function of wild type (WT) CRX, supporting an antimorphic mechanism. E168d2 and R90W are mechanistically distinct mouse models for CRX-associated disease that will allow the elucidation of molecular mechanisms and testing of novel therapeutic approaches for different forms of CRX-associated disease.

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Section: Discussionsupporting

confidence: 70%

Mechanistically Distinct Mouse Models for CRX-Associated Retinopathy

et al. 2014

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“…However, as Nrl expression is rapidly turned off in Crx Rip/+ mutants compared with that in Crx -/-mice, we propose that OTX2, and not CRX, is a major contributor for the initiation or maintenance of Nrl transcription in developing retinas. Indeed, RNA-Seq analysis (Supplemental Table 1) showed a small but statistically significant (P < 0.001) increase of Otx2 expression in Crx Rip/+ , Crx Rip/Rip , and Crx -/-retinas (1.6-, 2.9-, and 2.1-fold, respectively), indicating that OTX2 might compensate for the lack of CRX, as demonstrated in Drosophila (45). In addition, transcriptome analysis of flow-sorted WT mouse rod photoreceptors at P2 and P21 revealed continued (though reduced) expression of Otx2 (Table 2).…”

Section: Figurementioning

confidence: 85%

OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness

Roger¹,

Hiriyanna²,

Gotoh³

et al. 2014

J. Clin. Invest.

106

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Leber congenital amaurosis (LCA) encompasses a set of early-onset blinding diseases that are characterized by vision loss, involuntary eye movement, and nonrecordable electroretinogram (ERG). At least 19 genes are associated with LCA, which is typically recessive; however, mutations in homeodomain transcription factor CRX lead to an autosomal dominant form of LCA. The mechanism of CRX-associated LCA is not understood. Here, we identified a spontaneous mouse mutant with a frameshift mutation in Crx (Crx Rip ). We determined that Crx Rip is a dominant mutation that results in congenital blindness with nonrecordable response by ERG and arrested photoreceptor differentiation with no associated degeneration. Expression of LCA-associated dominant CRX frameshift mutations in mouse retina mimicked the Crx Rip phenotype, which was rescued by overexpression of WT CRX. Whole-transcriptome profiling using deep RNA sequencing revealed progressive and complete loss of rod differentiation factor NRL in Crx Rip retinas. Expression of NRL partially restored rod development in Crx Rip/+ mice. We show that the binding of homeobox transcription factor OTX2 at the Nrl promoter was obliterated in Crx Rip mice and ectopic expression of OTX2 rescued the rod differentiation defect. Together, our data indicate that OTX2 maintains Nrl expression in developing rods to consolidate rod fate. Our studies provide insights into CRX mutation-associated congenital blindness and should assist in therapeutic design.

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“…The role of Otd in the transcriptional activation of photosensitive protein components likely preceded the pancrustacean ancestor. This conjecture is based on the involvement of Otx factors in the development of the ciliary photoreceptors of vertebrates, the capacity of vertebrate Otx factors to rescue Otd functions in the Drosophila eye, and the multilayered master regulatory roles of Otd in pancrustacean photoreceptor differentiation [22,34,35,37,46,48,52,53]. It is therefore reasonable to assume that an ancestral Otx homolog was the regulator of the prototype photosensitive membrane compartment that harvested light through opsins in the earliest animal photoreceptors.…”

Section: A Developmental Model Of Photoreceptor Subtype Evolutionmentioning

confidence: 99%

Ancient default activators of terminal photoreceptor differentiation in the pancrustacean compound eye: the homeodomain transcription factors Otd and Pph13

Friedrich

Cook

Zelhof

2016

Current Opinion in Insect Science

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The origin of the Drosophila compound eye predates the ancestor of Pancrustacea, the arthropod clade that includes insects and Crustaceans. Recent studies in emerging model systems for pancrustacean development - the red flour beetle Tribolium castaneum and water flea Daphnia pulex - have begun to shed light on the evolutionary conservation of transcriptional mechanisms found for the Drosophila compound eye. Here, we discuss the conserved roles of the transcription factors Otd and Pph13, which complement each other in two terminal events of photoreceptor differentiation: rhabdomere morphogenesis and transcriptional default activation of opsin gene expression. The synthesis of these data allows us to frame an evolutionary developmental model of the earliest events that generated the wavelength-specific photoreceptor subtypes of pancrustacean compound eyes.

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OTX2 and CRX rescue overlapping and photoreceptor‐specific functions in the Drosophila eye

Cited by 28 publications

References 81 publications

Mechanistically Distinct Mouse Models for CRX-Associated Retinopathy

Mechanistically Distinct Mouse Models for CRX-Associated Retinopathy

OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness

Ancient default activators of terminal photoreceptor differentiation in the pancrustacean compound eye: the homeodomain transcription factors Otd and Pph13

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