title: Lens specific RLIP76 transgenic mice show a phenotype similar to microphthalmia.
abstract: RALBP1/RLIP76 is a ubiquitously expressed protein, involved in promotion and regulation of functions initiated by Ral and R-Ras small GTPases. Presence of multiple domains in its structure enables RLIP76 to be involved in a number of physiological processes such as endocytosis, exocytosis, mitochondrial fission, actin cytoskeleton remodeling, and transport of exogenous and endogenous toxicants. Previously, we have established that RLIP76 provides protection to ocular tissues against oxidative stress by transporting the glutathione-conjugates of the toxic, electrophilic products of lipid peroxidation generated during oxidative stress. Therefore, we developed lens specific RLIP76 transgenic mice (lensRLIP76 Tg) to elucidate the role of RLIP76 in protection against oxidative stress, but these transgenic mice showed impaired lens development and a phenotype with small eyes similar to that observed in microphthalmia. These findings prompted us to investigate the mechanisms via which RLIP76 affects lens and eye development. In the present study, we report engineering of lensRLIP76 Tg mice, characterization of the associated phenotype, and the possible molecular mechanisms that lead to the impaired development of eye and lens in these mice. The results of microarray array analysis indicate that the genes involved in pathways for G-Protein signaling, actin cytoskeleton reorganization, endocytosis, and apoptosis are affected in these transgenic mice. The expression of transcription factors, Pax6, Hsf1, and Hsf4b known to be involved in lens development is down regulated in the lens of these Tg mice. However, the expression of heat shock proteins (Hsps), the downstream targets of Hsfs, is differentially affected in the lens showing down regulation of Hsp27, Hsp40, up regulation of Hsp60, and no effect on Hsp70 and Hsp90 expression. The disruption in the organization of actin cytoskeleton of these Tg mice was associated with the inhibition of the activation of Cdc42 and down regulation of cofilin phosphorylation. These mice may provide useful animal model for elucidating the mechanisms of lens development, and etiology of microphthalmia.
authors.affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Sahu
authors.affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Division of Diabetes, Endocrinology & Metabolism, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope, National Medical Center, Duarte, CA 91010, USA.
authors.forename: Sushma
authors.initials: S
authors.lastname: Yadav
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Maki
authors.initials: M
authors.lastname: Wakamiya
authors.affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Chaudhary
authors.affiliation: Division of Diabetes, Endocrinology & Metabolism, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope, National Medical Center, Duarte, CA 91010, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Awasthi
authors.affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA. Electronic address: Yogesh.Awasthi@live.unthsc.edu.
authors.forename: Yogesh C
authors.initials: YC
authors.lastname: Awasthi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D020690:GTPase-Activating Proteins / Q000096:biosynthesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D007908:Lens, Crystalline / Q000002:abnormalities / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008850:Microphthalmos / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010641:Phenotype; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D020690:GTPase-Activating Proteins; C490620:Ralbp1 protein, mouse; D012313:RNA
keywords: Cdc42; Hsf1; Hsf4b; Pax6; RLIP76; cytoskeleton organization; lens development; microphthalmia