Neural and Angiogenic Defects in Eyes of Transgenic Mice Expressing a Dominant-Negative FGF Receptor in the Pigmented Cells

2000 ◽  
Vol 71 (4) ◽  
pp. 395-404 ◽  
Author(s):  
Benoı̂t Rousseau ◽  
David Dubayle ◽  
Florian Sennlaub ◽  
Jean-Claude Jeanny ◽  
Pierre Costet ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Dominant Negative ◽  
Fgf Receptor

FGF suppresses apoptosis and induces differentiation of fibre cells in the mouse lens

Development ◽  
1995 ◽  
Vol 121 (12) ◽  
pp. 4383-4393 ◽  
Author(s):  
R.L. Chow ◽  
G.D. Roux ◽  
M. Roghani ◽  
M.A. Palmer ◽  
D.B. Rifkin ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transgenic Mice ◽  
Dominant Negative ◽  
Fgf Receptor ◽  
Fibre Cell ◽  
Dominant Negative Form ◽  
Lens Fibre ◽  
Mouse Lens ◽  
Negative Form

To determine whether fibroblast growth factor (FGF) has a role in lens development, we have generated transgenic mice expressing a dominant-negative form of the murine FGF receptor-1 (FGFRDN) in the lens. Using the fibre cell-specific alpha A-crystallin promoter to express the FGFRDN, we have asked whether FGF is required for fibre cell differentiation. The transgenic mice display diminished differentiation of fibre cells as indicated by their reduced elongation. In addition, transgenic lenses have an unusual refractile anomaly that morphological and biochemical data show results from the apoptosis of fibre cells in the central region of the lens. These results show that lens fibre cells are dependent on FGF for their survival and differentiation, and demonstrate that growth factor deprivation in vivo can lead to apoptosis.

Expression of a truncated FGF receptor results in defective lens development in transgenic mice

Development ◽  
1995 ◽  
Vol 121 (12) ◽  
pp. 3959-3967 ◽  
Author(s):  
M.L. Robinson ◽  
L.A. MacMillan-Crow ◽  
J.A. Thompson ◽  
P.A. Overbeek
Keyword(s):  
Epithelial Cells ◽  
Transgenic Mice ◽  
Polymerase Chain Reaction Amplification ◽  
Dominant Negative ◽  
Lens Epithelial Cells ◽  
Type I ◽  
Lens Development ◽  
Fgf Receptor ◽  
Surface Receptors ◽  
Normal Lens

Members of the fibroblast growth factor (FGF) family are thought to initiate biological responses through the activation of cell surface receptors which must dimerize to transmit an intracellular signal. Mammalian lens epithelial cells respond to exogenous extracellular FGF, either in tissue culture or in transgenic mice, by initiating fiber cell differentiation. The role of FGF signalling in normal lens development was evaluated by lens-specific synthesis of a kinase-deficient FGF receptor type I (FGFR1) in transgenic mice. This truncated FGF receptor is thought to act as a dominant negative protein by heterodimerization with endogenous FGF receptors. The presence of transgenic mRNA in the lens was confirmed by in situ hybridization and by polymerase chain reaction amplification of reverse transcribed lens RNA (RT-PCR). The presence of transgenic protein was determined by Western blotting with antibodies to an extracellular domain of FGFR1. Three of four transgenic families expressing the truncated FGF receptor exhibited lens defects ranging from cataracts to severe microphthalmia. While the microphthalmic lenses displayed a normal pattern of differentiation-specific crystallin expression, the lens epithelial cells were reduced in number and the lens fiber cells displayed characteristics consistent with the induction of apoptosis. Our results support the view that FGF receptor signalling plays an essential role in normal lens biology.

Neuronal vulnerability in transgenic mice expressing an inducible dominant-negative FGF receptor

2006 ◽  
Vol 198 (2) ◽  
pp. 338-349 ◽  
Author(s):  
Felix P. Eckenstein ◽  
Toby McGovern ◽  
Drew Kern ◽  
Jason Deignan
Keyword(s):  
Transgenic Mice ◽  
Dominant Negative ◽  
Fgf Receptor

scholarly journals Targeted Expression of a Dominant-Negative Fibroblast Growth Factor (FGF) Receptor in Gonadotropin-Releasing Hormone (GnRH) Neurons Reduces FGF Responsiveness and the Size of GnRH Neuronal Population

2005 ◽  
Vol 19 (1) ◽  
pp. 225-236 ◽  
Author(s):  
Pei-San Tsai ◽  
Suzanne M. Moenter ◽  
Hector R. Postigo ◽  
Mohammed El Majdoubi ◽  
Toni R. Pak ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Neuronal Cell ◽  
Neuronal Population ◽  
Dominant Negative ◽  
Delayed Puberty ◽  
Fibroblast Growth ◽  
Gnrh Neuron ◽  
Fgf Receptor ◽  
Gnrh Neurons ◽  
A Cell

Abstract Increasing evidence suggests that fibroblast growth factors (FGFs) are neurotrophic in GnRH neurons. However, the extent to which FGFs are involved in establishing a functional GnRH system in the whole organism has not been investigated. In this study, transgenic mice with the expression of a dominant-negative FGF receptor mutant (FGFRm) targeted to GnRH neurons were generated to examine the consequence of disrupted FGF signaling on the formation of the GnRH system. To first test the effectiveness of this strategy, GT1 cells, a GnRH neuronal cell line, were stably transfected with FGFRm. The transfected cells showed attenuated neurite outgrowth, diminished FGF-2 responsiveness in a cell survival assay, and blunted activation of the signaling pathway in response to FGF-2. Transgenic mice expressing FGFRm in a GnRH neuron-specific manner exhibited a 30% reduction in GnRH neuron number, but the anatomical distribution of GnRH neurons was unaltered. Although these mice were initially fertile, they displayed several reproductive defects, including delayed puberty, reduced litter size, and early reproductive senescence. Overall, our results are the first to show, at the level of the organism, that FGFs are one of the important components involved in the formation and maintenance of the GnRH system.

scholarly journals Cellular Werner Phenotypes in Mice Expressing a Putative Dominant-Negative Human WRN Gene

Genetics ◽  
2000 ◽  
Vol 154 (1) ◽  
pp. 357-362
Author(s):  
Lan Wang ◽  
Charles E Ogburn ◽  
Carol B Ware ◽  
Warren C Ladiges ◽  
Hagop Youssoufian ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mice ◽  
Werner Syndrome ◽  
Dominant Negative ◽  
Dominant Negative Mutation ◽  
Fibroblast Cultures ◽  
Age Related

Abstract Mutations at the Werner helicase locus (WRN) are responsible for the Werner syndrome (WS). WS patients prematurely develop an aged appearance and various age-related disorders. We have generated transgenic mice expressing human WRN with a putative dominant-negative mutation (K577M-WRN). Primary tail fibroblast cultures from K577M-WRN mice showed three characteristics of WS cells: hypersensitivity to 4-nitroquinoline-1-oxide (4NQO), reduced replicative potential, and reduced expression of the endogenous WRN protein. These data suggest that K577M-WRN mice may provide a novel mouse model for the WS.

scholarly journals Intestinal Apolipoprotein A-IV Gene Transcription Is Controlled by Two Hormone-Responsive Elements: A Role for Hepatic Nuclear Factor-4 Isoforms

2005 ◽  
Vol 19 (9) ◽  
pp. 2320-2334 ◽  
Author(s):  
Amena Archer ◽  
Dominique Sauvaget ◽  
Valérie Chauffeton ◽  
Pierre-Etienne Bouchet ◽  
Jean Chambaz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transgenic Mice ◽  
Distal Region ◽  
Proximal Region ◽  
Dominant Negative ◽  
Specific Expression ◽  
Nuclear Factors ◽  
Dominant Negative Form ◽  
Responsive Element ◽  
Hormone Responsive Element

Abstract In the small intestine, the expression of the apolipoprotein (apo) C-III and A-IV genes is restricted to the enterocytes of the villi. We have previously shown that, in transgenic mice, specific expression of the human apo C-III requires a hormone-responsive element (HRE) located in the distal region of the human apoA-IV promoter. This HRE binds the hepatic nuclear factors (HNF)-4α and γ. Here, intraduodenal injections in mice and infections of human enterocytic Caco-2/TC7 cells with an adenovirus expressing a dominant-negative form of HNF-4α repress the expression of the apoA-IV gene, demonstrating that HNF-4 controls the apoA-IV gene expression in enterocytes. We show that HNF-4α and γ functionally interact with a second HRE present in the proximal region of the human apoA-IV promoter. New sets of transgenic mice expressing mutated forms of the promoter, combined with the human apo C-III enhancer, demonstrate that, whereas a single HRE is sufficient to reproduce the physiological cephalo-caudal gradient of apoA-IV gene expression, both HREs are required for expression that is restricted to villi. The combination of multiple HREs may specifically recruit regulatory complexes associating HNF-4 and either coactivators in villi or corepressors in crypts.

scholarly journals Expression of a Dominant Negative Mutant of Interleukin-1β Converting Enzyme in Transgenic Mice Prevents Neuronal Cell Death Induced by Trophic Factor Withdrawal and Ischemic Brain Injury

1997 ◽  
Vol 185 (5) ◽  
pp. 933-940 ◽  
Author(s):  
Robert M. Friedlander ◽  
Valeria Gagliardini ◽  
Hideaki Hara ◽  
Klaus B. Fink ◽  
Weiwei Li ◽  
...  
Keyword(s):  
Brain Injury ◽  
Transgenic Mice ◽  
Dorsal Root ◽  
Neuron Specific Enolase ◽  
Dominant Negative ◽  
Trophic Factor ◽  
Dominant Negative Mutant ◽  
Lacz Gene ◽  
Converting Enzyme ◽  
Induced Apoptosis

To explore the role of the interleukin (IL)-1β converting enzyme (ICE) in neuronal apoptosis, we designed a mutant ICE gene (C285G) that acts as a dominant negative ICE inhibitor. Microinjection of the mutant ICE gene into embryonal chicken dorsal root ganglial neurons inhibits trophic factor withdrawal–induced apoptosis. Transgenic mice expressing the fused mutant ICE-lacZ gene under the control of the neuron specific enolase promoter appeared neurologically normal. These mice are deficient in processing pro–IL-1β, indicating that mutant ICEC285G blocks ICE function. Dorsal root ganglial neurons isolated from transgenic mice were resistant to trophic factor withdrawal–induced apoptosis. In addition, the neurons isolated from newborn ICE knockout mice are similarly resistant to trophic factor withdrawal–induced apoptosis. After permanent focal ischemia by middle cerebral artery occlusion, the mutant ICEC285G transgenic mice show significantly reduced brain injury as well as less behavioral deficits when compared to the wild-type controls. Since ICE is the only enzyme with IL-1β convertase activity in mice, our data indicates that the mutant ICEC285G inhibits ICE, and hence mature IL-1β production, and through this mechanism, at least in part, inhibits apoptosis. Our data suggest that genetic manipulation using ICE family dominant negative inhibitors can ameliorate the extent of ischemia-induced brain injury and preserve neurological function.

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