Partial rescue of the ocular retardation phenotype by genetic modifiers

Bone-Larson, Cynthia L.; Basu, Sharmila; Radel, Jeff; Liang, Mei-Ying; Perozek, Timothy; Kapousta-Bruneau, Natalia V.; Green, Daniel G.; Burmeister, Margit; Hankin, Mark

doi:10.1002/(sici)1097-4695(20000205)42:2<232::aid-neu7>3.0.co;2-4

Cited by 41 publications

(44 citation statements)

References 28 publications

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“…Tuj1 expression is more centrally restricted (Fig. 5G) consistent with a delay in neurogenesis (Bone-Larson et al, 2000;Rutherford et al, 2004;Green et al, submitted). Pax6 is widely expressed in a pattern consistent with RPCs, and this could be due to developmental delay (Fig.…”

Section: Vsx1 Fails To Compensate For the Loss Of Chx10 Function Durisupporting

confidence: 53%

“…Mutations in Chx10 cause microphthalmia in humans (Bar-Yosef et al, 2004;Ferda Percin et al, 2000) and mice (Burmeister et al, 1996), and antisensechx10 RNA injected into zebrafish embryos causes a small eye phenotype (Barabino et al, 1997). Studies in ocular retardation J (orJ) mice, which carry a spontaneously-derived nonsense mutation in the HD (Y176stop) of Chx10 (Chx10 orJ ; Burmeister et al, 1996;Theiler et al, 1976), show that in addition to a lack of bipolar cells, the Chx10 orJ homozygote (Chx10 orJ/orJ ) retina exhibits a profound decrease in RPC proliferation, a propensity to transdifferentiate along a pigmentation pathway, delays in embryonic neurogenesis, persistent neurogenesis in the adult retina, and an enrichment of adult ciliary epithelium derived retinal stem cells (Bone-Larson et al, 2000;Burmeister et al, 1996;Coles et al, 2006;Dhomen et al, 2006;Green et al, 2003;Horsford et al, 2005;Livne-Bar et al, 2006;Rowan et al, 2004;Rutherford et al, 2004).…”

Section: Introduction1mentioning

confidence: 97%

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Negative regulation of Vsx1 by its paralog Chx10/Vsx2 is conserved in the vertebrate retina

et al. 2008

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Chx10-and Vsx1 are the only Paired-like CVC (Prd-L:CVC) homeobox genes in the mouse genome. Both are expressed in the retina and have important but distinct roles in retinal development. Mutations in Chx10 cause reduced retinal progenitor cell (RPC) proliferation and an absence of bipolar cells, while mutations in Vsx1 impair differentiation of cone bipolar cells. Given their structural similarities and importance in retinal development, we sought to determine if a regulatory interaction exists between these genes and whether inactivation of both genes blocks initiation of retinal development. We found that Chx10 binds to a specific sequence in the Vsx1 5′-intergenic region and represses the activity of a luciferase reporter under the control of the Vsx1 promoter. This is consistent with our observation that there is an inverse relationship between the levels of Chx10 and Vsx1 immunostaining within the bipolar cell class. Furthermore, Vsx1 mRNA is upregulated in the RPCs of Chx10 deficient mice and zebrafish embryos injected with a chx10 morpholino. In mice deficient for both Chx10 and Vsx1 and zebrafish embryos coinjected with chx10 and vsx1 morpholinos, the changes in embryonic retinal development and marker expression are similar in magnitude to embryos with Chx10 loss of function only. From these studies, we propose that Vsx1 is a direct target of Chx10-mediated transcriptional repression. Although Vsx1 mRNA is upregulated in Chx10 deficient RPCs, Vsx1 does not genetically compensate for loss of Chx10, demonstrating that Prd-L:CVC genes, although important, are not absolutely required to initiate retinal development.

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Section: Vsx1 Fails To Compensate For the Loss Of Chx10 Function Durisupporting

confidence: 53%

Section: Introduction1mentioning

confidence: 97%

Negative regulation of Vsx1 by its paralog Chx10/Vsx2 is conserved in the vertebrate retina

et al. 2008

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“…(Burmeister et al, 1996). This phenotype correlates with a reduction in proliferation of retinal progenitor cells, especially those in the periphery of the retina (Bone-Larson et al, 2000;Burmeister et al, 1996). The central retina does appear to undergo differentiation, but the retina differentiates into a poorly laminated structure (Bone-Larson et al, 2000;Burmeister et al, 1996).…”

Section: Introductionsupporting

confidence: 53%

“…Molecular analysis has revealed the absence of bipolar cells in these retinas, although all other cell types could be found (Burmeister et al, 1996). Several peripheral structures of the eye are abnormal in or J mice, including the ciliary body and iris, and the lens is cataracterous (Bone-Larson et al, 2000;Tropepe et al, 2000). The ciliary body appears to be expanded at the periphery of the retina, but does not undergo proper morphogenesis.…”

Section: Introductionmentioning

confidence: 92%

Transdifferentiation of the retina into pigmented cells in ocular retardation mice defines a new function of the homeodomain geneChx10

et al. 2004

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The homeodomain transcription factor Chx10 is one of the earliest markers of the developing retina. It is required for retinal progenitor cell proliferation as well as formation of bipolar cells, a type of retinal interneuron. orJ (ocular retardation) mice, which are Chx10 null mutants, are microphthalmic and show expanded and abnormal peripheral structures, including the ciliary body. We show here, in a mixed genetic background, the progressive appearance of pigmented cells in the neural retina, concomitant with loss of expression of retinal markers. Fate mapping analysis using a multifunctional Chx10 BAC reporter mouse revealed this process to be direct transdifferentiation of retinal cells into pigmented cells. Microarray and in situ hybridization analyses revealed a complex program underlying the transdifferentiation. This program involved the expansion of expression of genes normally found only in the periphery into central regions of the eye. These genes included a transcription factor controlling pigmentation, Mitf, and the related factor Tfec(Tcfec – Mouse Genome Informatics), which can activate a melanogenic gene expression program. Misexpression of Chx10 in the developing retinal pigmented epithelium (RPE) caused downregulation of Mitf, Tfec, and associated pigment markers, leading to a nonpigmented RPE. These data link Chx10 and Mitf to maintenance of the neural retina and RPE fates respectively. Further, they suggest a new role for Chx10 in maintenance of compartment boundaries in the peripheral retina.

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“…Gross abnormalities shared between Chx10-null humans and mice include small eyes, cataracts, iris coloboma and blindness (Ferda Percin et al, 2000;Robb et al, 1978). Although the whole eye is affected by loss of Chx10 function, the primary genetic defect is specific to the retina and is characterized by two major developmental defects: a dramatic reduction in retinal cell number and an absence of bipolar interneurons (Bone-Larson et al, 2000;Burmeister et al, 1996;Konyukhov and Sazhina, 1971). Although it has been suggested that Chx10 acts in combination with the neurogenic bHLH gene Mash1 (Ascl1 -Mouse Genome Informatics) to promote the bipolar cell fate (Hatakeyama et al, 2001), the function of Chx10 in regulating cell number is unknown.…”

Section: Introductionmentioning

confidence: 92%

Genetic rescue of cell number in a mouse model of microphthalmia:interactions between Chx10 and G1-phase cell cycle regulators

2003

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Insufficient cell number is a primary cause of failed retinal development in the Chx10 mutant mouse. To determine if Chx10 regulates cell number by antagonizing p27 Kip1 activity, we generated Chx10, p27 Kip1 double null mice. The severe hypocellular defect in Chx10 single null mice is alleviated in the double null, and while Chx10-null retinas lack lamination, double null retinas have near normal lamination. Bipolar cells are absent in the double null retina, a defect that is attributable to a requirement for Chx10 that is independent of p27 Kip1 . We find that p27 Kip1 is abnormally present in progenitors of Chx10-null retinas, and that its ectopic localization is responsible for a significant amount of the proliferation defect in this microphthalmia model system. mRNA and protein expression patterns in these mice and in cyclin D1-null mice suggest that Chx10 influences p27 Kip1 at a posttranscriptional level, through a mechanism that is largely dependent on cyclin D1. This is the first report of rescue of retinal proliferation in a microphthalmia model by deletion of a cell cycle regulatory gene.

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Partial rescue of the ocular retardation phenotype by genetic modifiers

Cited by 41 publications

References 28 publications

Negative regulation of Vsx1 by its paralog Chx10/Vsx2 is conserved in the vertebrate retina

Negative regulation of Vsx1 by its paralog Chx10/Vsx2 is conserved in the vertebrate retina

Transdifferentiation of the retina into pigmented cells in ocular retardation mice defines a new function of the homeodomain geneChx10

Genetic rescue of cell number in a mouse model of microphthalmia:interactions between Chx10 and G1-phase cell cycle regulators

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