Mechanistically distinct mouse models for CRX-associated retinopathy.
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 Lebe...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-02-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3916252?pdf=render |
| _version_ | 1818488068163764224 |
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| author | Nicholas M Tran Alan Zhang Xiaodong Zhang Julie B Huecker Anne K Hennig Shiming Chen |
| author_facet | Nicholas M Tran Alan Zhang Xiaodong Zhang Julie B Huecker Anne K Hennig Shiming Chen |
| author_sort | Nicholas M Tran |
| collection | DOAJ |
| description | 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: Crx(E168d2) ("E168d2") and Crx(R90W) ("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. |
| first_indexed | 2024-12-10T16:46:18Z |
| format | Article |
| id | doaj.art-70ee4e7ca77543bb9f07edb01c3141ad |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-10T16:46:18Z |
| publishDate | 2014-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-70ee4e7ca77543bb9f07edb01c3141ad2022-12-22T01:41:02ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042014-02-01102e100411110.1371/journal.pgen.1004111Mechanistically distinct mouse models for CRX-associated retinopathy.Nicholas M TranAlan ZhangXiaodong ZhangJulie B HueckerAnne K HennigShiming ChenCone-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: Crx(E168d2) ("E168d2") and Crx(R90W) ("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.http://europepmc.org/articles/PMC3916252?pdf=render |
| spellingShingle | Nicholas M Tran Alan Zhang Xiaodong Zhang Julie B Huecker Anne K Hennig Shiming Chen Mechanistically distinct mouse models for CRX-associated retinopathy. PLoS Genetics |
| title | Mechanistically distinct mouse models for CRX-associated retinopathy. |
| title_full | Mechanistically distinct mouse models for CRX-associated retinopathy. |
| title_fullStr | Mechanistically distinct mouse models for CRX-associated retinopathy. |
| title_full_unstemmed | Mechanistically distinct mouse models for CRX-associated retinopathy. |
| title_short | Mechanistically distinct mouse models for CRX-associated retinopathy. |
| title_sort | mechanistically distinct mouse models for crx associated retinopathy |
| url | http://europepmc.org/articles/PMC3916252?pdf=render |
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