Forebrain-specific knockout of B-raf kinase leads to deficits in hippocampal long-term potentiation, learning, and memory

Chen, Adele P.; Ohno, Minoru; Giese, K. Peter; Kühn, Ralf; Chen, Rachel L.; Silva, Alcino J.

doi:10.1002/jnr.20703

Cited by 69 publications

(78 citation statements)

References 57 publications

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“…Cre + ;p300 flox/flox mice do not show gross morphological abnormalities or reduced size compared to control littermates, and the expected Mendelian ratio of genotypes was observed suggesting no developmental defects in these mice (data not shown). Importantly, it has previously been shown that mice expressing Cre recombinase in the forebrain do not exhibit learning and memory deficits (Chen et al 2006).…”

Section: Resultsmentioning

confidence: 99%

Subregion-specific p300 conditional knock-out mice exhibit long-term memory impairments

Oliveira¹,

Estévez²,

Hawk³

et al. 2011

Learn. Mem.

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Histone acetylation plays a critical role during long-term memory formation. Several studies have demonstrated that the histone acetyltransferase (HAT) CBP is required during long-term memory formation, but the involvement of other HAT proteins has not been extensively investigated. The HATs CBP and p300 have at least 400 described interacting proteins including transcription factors known to play a role in long-term memory formation. Thus, CBP and p300 constitute likely candidates for transcriptional coactivators in memory formation. In this study, we took a loss-of-function approach to evaluate the role of p300 in long-term memory formation. We used conditional knock-out mice in which the deletion of p300 is restricted to the postnatal phase and to subregions of the forebrain. We found that p300 is required for the formation of long-term recognition memory and long-term contextual fear memory in the CA1 area of the hippocampus and cortical areas.

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Section: Resultsmentioning

confidence: 99%

Subregion-specific p300 conditional knock-out mice exhibit long-term memory impairments

Oliveira¹,

Estévez²,

Hawk³

et al. 2011

Learn. Mem.

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“…B-Raf ablation affects tumor development in RIP1Tag2 mice RIP-Cre;b-raf f/f mice (BbKO, B-Raf deleted in b cells) were generated by mating the RIP-Cre mouse strain (Ahlgren et al, 1998) with a b-raf f/f line (Chen et al, 2006;Galabova-Kovacs et al, 2006b). Partial conversion of the b-raf flox to the b-raf D allele was observed in pancreata from these mice, but not in other organs (Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

“…Mice and genotyping b-raf f/f (Chen et al, 2006), Rip-Cre (Ahlgren et al, 1998) and RIP1Tag2 transgenic mice (Hanahan, 1985) have been previously described. All mice were backcrossed to 129Sv background for a minimum of seven generations.…”

Section: Methodsmentioning

confidence: 99%

B-Raf is required for ERK activation and tumor progression in a mouse model of pancreatic β-cell carcinogenesis

et al. 2008

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Activation of the Raf/MEK/ERK pathway, often by gainof-function mutations of RAS or RAF, is observed in many human cancers. The extracellular signal-regulated kinase (ERK) pathway is required for the proliferation of cancer cell lines harboring activating BRAF or, to a lesser extent, activating RAS mutations. It is still unclear, however, whether the pathway is required in vivo for tumor development, particularly in tumors in which B-Raf is not mutationally activated. During embryonic development, B-Raf is essential for angiogenesis in the placenta. To address the question of whether B-Raf contributed to tumor angiogenesis in vivo we conditionally ablated B-Raf in a model of pancreatic islet carcinoma driven by the functional inactivation of tumor suppressors (RIP1Tag2), which critically depends on angiogenesis for growth. We find that B-Raf is dispensable for the proliferation of tumor cells in culture, but necessary for ERK activation and for the expression of angiogenic factors by tumor cells in vivo and in vitro. In vivo, these defects result in the formation of hollow tumors with decreased vessel density and strongly reduced proliferation. The progression from adenoma to carcinoma is also significantly impaired. Thus, endogenous B-Raf contributes to the development of RIP1Tag2 tumors by supporting the stromal response and tumor progression.

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“…To circumvent early embryonic lethality by B-raf inactivation, a conditionally targeted B-raf allele (B-raf f ) was generated (22). B-raf f (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…B-raf f/f (22) and c-raf-1 f/f (41) mice were maintained on a 129͞Sv background and crossed to mice expressing the Cre recombinase from the Mox-2 locus (23) for epiblast-restricted ablation. For endothelial-cell-restricted ablation, B-raf f/f animals were bred to transgenic mice expressing Cre under the control of the Tie2 promoter (35) (kind gift of Bernd Arnold, Heidelberg).…”

Section: Methodsmentioning

confidence: 99%

Essential role of B-Raf in ERK activation during extraembryonic development

Galabova-Kovacs

Matzen

Piazzolla

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The kinases of the Raf family have been intensively studied as activators of the mitogen-activated protein kinase kinase͞extra-cellular signal-regulated kinase (ERK) module in regulated and deregulated proliferation. Genetic evidence that Raf is required for ERK activation in vivo has been obtained in lower organisms, which express only one Raf kinase, but was hitherto lacking in mammals, which express more than one Raf kinase. Ablation of the two best studied Raf kinases, B-Raf and Raf-1, is lethal at midgestation in mice, hampering the detailed study of the essential functions of these proteins. Here, we have combined conventional and conditional gene ablation to show that B-Raf is essential for ERK activation and for vascular development in the placenta. B-Rafdeficient placentae show complete absence of phosphorylated ERK and strongly reduced HIF-1␣ and VEGF levels, whereas all these parameters are normal in Raf-1-deficient placentae. In addition, neither ERK phosphorylation nor development are affected in B-raf-deficient embryos that are born alive obtained by epiblastrestricted gene inactivation. The data demonstrate that B-Raf plays a nonredundant role in ERK activation during extraembyronic mammalian development in vivo.T he placenta is the first organ to develop during embryogenesis, and it supports the growth of the developing embryo by mediating the exchange of nutrients and wastes between the fetal and maternal circulatory systems. Placentation includes extensive angiogenesis, and reduced placental vascular development is associated with early embryonic mortality. Genetic studies have demonstrated a crucial role of VEGF, FGF, and their receptors in placental angiogenesis. In addition, the ablation of several signaling molecules operating downstream of receptor tyrosine kinases results in defects in placentation, often at the stage of labyrinth formation (1).The Raf kinases (A-Raf, B-Raf, and Raf-1) relay signals from tyrosine kinase receptors to the mitogen-activated protein kinase kinase (MEK)͞extracellular signal-regulated kinase (ERK) signaling module. Although most of the early work on the activation of the MEK͞ERK module was focused on Raf-1, evidence has accumulated that B-Raf is the main MEK kinase. Raf kinases from lower organisms (Caenorhabditis elegans lin-45 and Drosophila D-Raf ) are more similar to B-Raf than to the other two mammalian Raf kinases. Biochemical studies have indicated that B-Raf is the main MEK kinase found in fibroblast and brain lysates (2-5). Consistently, among the three Raf kinases, B-Raf binds best to MEK (6) and has the highest basal MEK kinase activity, both in vitro (7) and in fibroblasts, when expressed as a conditionally oncogenic form (8). Finally, B-Raf mutations resulting in increased MEK͞ERK activation have been discovered in a broad range of human tumors (9). All these observations hint at B-Raf as the archetypal mammalian MEK kinase, whereas Raf-1 and A-Raf have probably diverged to perform other functions. Growth-factor-stimulated ERK activation is reduced...

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Forebrain-specific knockout of B-raf kinase leads to deficits in hippocampal long-term potentiation, learning, and memory

Cited by 69 publications

References 57 publications

Subregion-specific p300 conditional knock-out mice exhibit long-term memory impairments

Subregion-specific p300 conditional knock-out mice exhibit long-term memory impairments

B-Raf is required for ERK activation and tumor progression in a mouse model of pancreatic β-cell carcinogenesis

Essential role of B-Raf in ERK activation during extraembryonic development

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