Dataset Information

Effects of elevated Pax6 expression and genetic background on mouse eye development.

ABSTRACT: PURPOSE:To analyze the effects of Pax6 overexpression and its interaction with genetic background on eye development. METHODS:Histologic features of eyes from hemizygous PAX77(+/-) transgenic (high Pax6 gene dose) and wild-type mice were compared on different genetic backgrounds. Experimental PAX77(+/-)<-->wild-type and control wild-type<-->wild-type chimeras were analyzed to investigate the causes of abnormal eye development in PAX77(+/-) mice. RESULTS:PAX77(+/-) mice showed an overlapping but distinct spectrum of eye abnormalities to Pax6(+/-) heterozygotes (low Pax6 dose). Some previously reported PAX77(+/-) eye abnormalities did not occur on all three genetic backgrounds examined. Several types of eye abnormalities occurred in the experimental PAX77(+/-)<-->wild-type chimeras, and they occurred more frequently in chimeras with higher contributions of PAX77(+/-) cells. Groups of RPE cells intruded into the optic nerve sheath, indicating that the boundary between the retina and optic nerve may be displaced. Both PAX77(+/-) and wild-type cells were involved in this ingression and in retinal folds, suggesting that neither effect was cell-autonomous. Cell-autonomous effects included failure of PAX77(+/-) and wild-type cells to mix normally and overrepresentation of PAX77(+/-) in the lens epithelium and RPE. CONCLUSIONS:The extent of PAX77(+/-) eye abnormalities depended on PAX77(+/-) genotype, genetic background, and stochastic variation. Chimera analysis identified two types of cell-autonomous effects of the PAX77(+/-) genotype. Abnormal cell mixing between PAX77(+/-) and wild-type cells suggests altered expression of cell surface adhesion molecules. Some phenotypic differences between PAX77(+/-)<-->wild-type and Pax6(+/-)<-->wild-type chimeras may reflect differences in the levels of PAX77(+/-) and Pax6(+/-) contributions to chimeric lenses.

SUBMITTER: Chanas SA

PROVIDER: S-EPMC2763115 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effects of elevated Pax6 expression and genetic background on mouse eye development.

Chanas Simon A SA Collinson J Martin JM Ramaesh Thaya T Dorà Natalie N Kleinjan Dirk A DA Hill Robert E RE West John D JD

Investigative ophthalmology & visual science 20090422 9

<h4>Purpose</h4>To analyze the effects of Pax6 overexpression and its interaction with genetic background on eye development.<h4>Methods</h4>Histologic features of eyes from hemizygous PAX77(+/-) transgenic (high Pax6 gene dose) and wild-type mice were compared on different genetic backgrounds. Experimental PAX77(+/-)<-->wild-type and control wild-type<-->wild-type chimeras were analyzed to investigate the causes of abnormal eye development in PAX77(+/-) mice.<h4>Results</h4>PAX77(+/-) mice show ...[more]

PMID: 19387074

Similar Datasets

Project description:Glutathione (GSH) is a critical endogenous antioxidant that protects against intracellular oxidative stress. As such, pathological alterations in GSH levels are linked to a myriad of diseases including cancer, neurodegeneration and cataract. The rate limiting step in GSH biosynthesis is catalyzed by the glutamate cysteine ligase catalytic subunit (GCLC). The high expression of GCLC in the lens supports the synthesis of millimolar concentrations of GSH in this tissue. Herein, we describe the morphological consequences of deleting (knocking out) Gclc from surface ectoderm-derived ocular tissues (using the Le-Cre transgene; Gclc KO) which includes an overt microphthalmia phenotype and severely disrupted formation of multiple ocular structures (i.e., cornea, iris, lens, retina). Controlling for the Le-Cre transgene revealed that the deletion of Gclc significantly exacerbated the microphthalmia phenotype in Le-Cre hemizygous mice and resulted in dysregulated gene expression that was unique to only the lenses of KO mice. We further characterized the impaired lens development by conducting an RNA-seq experiment on KO and Gclc control (CON) mouse lens at the day of birth. RNA-sequencing revealed significant differences between Gclc knockout (KO) and Gclc control (CON) lenses, including down-regulation of crystallins and lens fiber cell identity genes, and up-regulation of lens epithelial cell identity genes. In addition, genes related to the immune system (e.g., immune system process, inflammatory response, neutrophil chemotaxis) were upregulated, and genes related to eye/lens development were downregulated. TRANSFAC analysis of differentially expressed genes (DEGs) in the lens of Gclc KO mice implicated PAX6 as a key upstream regulator of Gclc KO sensitive genes. This was further supported by a strong positive correlation between the transcriptomes of the lenses of Gclc KO and Pax6 KO mice. Strikingly, the dysregulation of PAX6-regulated genes in Gclc KO mice was observed despite no change in the ocular localization of PAX6 or decrease in the expression of PAX6 in the lens. In vitro experiments demonstrated that suppression of intracellular GSH concentrations resulted in impairment of PAX6 transactivation activity. Taken together, the present results elucidate a novel mechanism wherein intracellular GSH concentrations may modulate PAX6 activity.

Dataset Information

Effects of elevated Pax6 expression and genetic background on mouse eye development.

Publications

Effects of elevated Pax6 expression and genetic background on mouse eye development.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets