scholarly journals Dominant-Negative Attenuation of cAMP-Selective Phosphodiesterase PDE4D Action Affects Learning and Behavior

2020 ◽  
Vol 21 (16) ◽  
pp. 5704
Author(s):  
Graeme B. Bolger ◽  
Lisa High Mitchell Smoot ◽  
Thomas van Groen

PDE4 cyclic nucleotide phosphodiesterases reduce 3′, 5′ cAMP levels in the CNS and thereby regulate PKA activity and the phosphorylation of CREB, fundamental to depression, cognition, and learning and memory. The PDE4 isoform PDE4D5 interacts with the signaling proteins β-arrestin2 and RACK1, regulators of β2-adrenergic and other signal transduction pathways. Mutations in PDE4D in humans predispose to acrodysostosis, associated with cognitive and behavioral deficits. To target PDE4D5, we developed mice that express a PDE4D5-D556A dominant-negative transgene in the brain. Male transgenic mice demonstrated significant deficits in hippocampus-dependent spatial learning, as assayed in the Morris water maze. In contrast, associative learning, as assayed in a fear conditioning assay, appeared to be unaffected. Male transgenic mice showed augmented activity in prolonged (2 h) open field testing, while female transgenic mice showed reduced activity in the same assay. Transgenic mice showed no demonstrable abnormalities in prepulse inhibition. There was also no detectable difference in anxiety-like behavior, as measured in the elevated plus-maze. These data support the use of a dominant-negative approach to the study of PDE4D5 function in the CNS and specifically in learning and memory.

2011 ◽  
Vol 225 (1) ◽  
pp. 305-310 ◽  
Author(s):  
Taku Nagai ◽  
Yuko Kitahara ◽  
Daisuke Ibi ◽  
Toshitaka Nabeshima ◽  
Akira Sawa ◽  
...  

Genetics ◽  
2000 ◽  
Vol 154 (1) ◽  
pp. 357-362
Author(s):  
Lan Wang ◽  
Charles E Ogburn ◽  
Carol B Ware ◽  
Warren C Ladiges ◽  
Hagop Youssoufian ◽  
...  

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.


2005 ◽  
Vol 19 (9) ◽  
pp. 2320-2334 ◽  
Author(s):  
Amena Archer ◽  
Dominique Sauvaget ◽  
Valérie Chauffeton ◽  
Pierre-Etienne Bouchet ◽  
Jean Chambaz ◽  
...  

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.


1997 ◽  
Vol 185 (5) ◽  
pp. 933-940 ◽  
Author(s):  
Robert M. Friedlander ◽  
Valeria Gagliardini ◽  
Hideaki Hara ◽  
Klaus B. Fink ◽  
Weiwei Li ◽  
...  

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.


2003 ◽  
Vol 284 (3) ◽  
pp. G525-G535 ◽  
Author(s):  
Christoph Schramm ◽  
Martina Protschka ◽  
Heinz H. Köhler ◽  
Jürgen Podlech ◽  
Matthias J. Reddehase ◽  
...  

In autoimmune hepatitis, strong TGF-β1 expression is found in the inflamed liver. TGF-β overexpression may be part of a regulatory immune response attempting to suppress autoreactive T cells. To test this hypothesis, we determined whether impairment of TGF-β signaling in T cells leads to increased susceptibility to experimental autoimmune hepatitis (EAH). Transgenic mice of strain FVB/N were generated expressing a dominant-negative TGF-β type II receptor in T cells under the control of the human CD2 promoter/locus control region. On induction of EAH, transgenic mice showed markedly increased portal and periportal leukocytic infiltrations with hepatocellular necroses compared with wild-type mice (median histological score = 1.8 ± 0.26 vs. 0.75 ± 0.09 in wild-type mice; P < 0.01). Increased IFN-γ production (118 vs. 45 ng/ml) and less IL-4 production (341 vs. 1,256 pg/ml) by mononuclear cells isolated from transgenic livers was seen. Impairment of TGF-β signaling in T cells therefore leads to increased susceptibility to EAH in mice. This suggests an important role for TGF-β in immune homeostasis in the liver and may teleologically explain TGF-β upregulation in response to T cell-mediated liver injury.


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