Hippocampus-dependent learning and memory is impaired in mice lacking the Ras-guanine-nucleotide releasing factor 1 (Ras-GRF1)

Giese, K. Peter; Friedman, Eugenia; Telliez, Jean‐Baptiste; Fedorov, N. A.; Wines, Mary E.; Feig, Larry A.; Silva, Alcino J.

doi:10.1016/s0028-3908(01)00096-x

Cited by 139 publications

(136 citation statements)

References 44 publications

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“…One other GEF has been tested in behavioral assays to date: Ras-GRF1 Ϫ/Ϫ mice have hippocampus-dependent learning and memory defects (40). Ras-GRF1 has dual Ras-and Rac-GEF domains, and it is unknown which confers the behavioral defects (40).…”

Section: Discussionmentioning

confidence: 99%

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P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination

Donald

Humby²,

Fyfe³

et al. 2008

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

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The small GTPase Rac controls cell morphology, gene expression, and reactive oxygen species formation. Manipulations of Rac activity levels in the cerebellum result in motor coordination defects, but activators of Rac in the cerebellum are unknown. P-Rex family guanine-nucleotide exchange factors activate Rac. We show here that, whereas P-Rex1 expression within the brain is widespread, P-Rex2 is specifically expressed in the Purkinje neurons of the cerebellum. We have generated P-Rex2 ؊/؊ and P-Rex1 ؊/؊ /PRex2 ؊/؊ mice, analyzed their Purkinje cell morphology, and assessed their motor functions in behavior tests. The main dendrite is thinned in Purkinje cells of P-Rex2 ؊/؊ pups and dendrite structure appears disordered in Purkinje cells of adult P-Rex2 ؊/؊ and P-Rex1 ؊/؊ /P-Rex2 ؊/؊ mice. P-Rex2 ؊/؊ mice show a mild motor coordination defect that progressively worsens with age and is more pronounced in females than in males. P-Rex1 ؊/؊ /P-Rex2 ؊/؊ mice are ataxic, with reduced basic motor activity and abnormal posture and gait, as well as impaired motor coordination even at a young age. We conclude that P-Rex1 and P-Rex2 are important regulators of Purkinje cell morphology and cerebellar function.G protein-coupled receptor ͉ guanine-nucleotide exchange factor ͉ phosphoinositide-3-kinase ͉ small GTPase Rac ͉ ataxia T he small GTPase Rac (isoforms 1, 2, and 3) controls the structure of the actomyosin cytoskeleton, gene expression, and reactive oxygen species (ROS) formation (1). In the nervous system, Rac is essential for all stages of neuronal development (neurite, axon, and dendrite formation, axon pathfinding, dendrite branching and dendritic spine formation, and survival), as shown by manipulations of Rac activity in the nervous system of animals, neuronal cell lines, and primary cultures (2).Deletion of the ubiquitous Rac1 from the mouse, whether total or specifically in the brain, is embryonic lethal (3, 4), but transgenic overexpression of constitutively active Rac1 in the Purkinje neurons of the cerebellum results in severe ataxia, with animals unable to walk in a straight line and poor performance on the rotarod (5). Similarly, deletion of nervous system-specific Rac3 results in an increased ability for learning and coordination of skilled movements (6), deletion of the Rac-GAP ␣-Chimerin induces a hopping gait due to misguidance of corticospinal tract axons (7), and deletion of the brain-specific form of the Rac-effector Wave, which links Rac to the actin cytoskeleton, causes defects in motor coordination, learning, and memory (8).Like all small GTPases, Rac is activated by guanine-nucleotide exchange factors (GEFs) (9). Several Rac-GEFs are known to control neuronal development: Tiam1/Stef regulates neurite and axon outgrowth and dendritic spine formation (2, 10); Vav2 and Vav3 control axon outgrowth from retina to thalamus (11); Trio governs neurite outgrowth, axon extension, and pathfinding (2); Kalirin regulates neurite and axon outgrowth and dendritic spine formation (2); Dock180 controls neurite ou...

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Section: Discussionmentioning

confidence: 99%

“…Ras-GRF1 has dual Ras-and Rac-GEF domains, and it is unknown which confers the behavioral defects (40).…”

Section: Discussionmentioning

confidence: 99%

P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination

Donald

Humby²,

Fyfe³

et al. 2008

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

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“…Additionally, a number of mutations of upstream regulators of ERK signaling, including Ras , the Neurofibromin GTPase Activating Protein (NF1) Costa et al, 2001Costa et al, , 2002, the guanine-nucleotide-releasing-factor (GRF) (Brambilla et al, 1997;Giese et al, 2001), and the B-Raf kinase disrupt LTP, learning, and memory. It is important to note that these signaling events may modulate both excitatory and inhibitory synaptic function.…”

Section: Erk Signalingmentioning

confidence: 99%

Molecular and cellular cognitive studies of the role of synaptic plasticity in memory

2002

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Synaptic plasticity has a central rolein nearly all models of learning and memory. Besides experiments documenting changes in synaptic function during learning, most of the evidence supporting a role for synaptic plasticity in memory comes from manipulations that either enhance or lesion synaptic processes. In the last decade, mouse transgenetics (knock outs and transgenics) have provided compelling evidence that the molecular mechanisms responsible for the induction and stability of synaptic changes have a critical role in the acquisition and storage of information. Here, I will review this literature, with a special focus on studies of hippocampal-dependent learning and memory.

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“…For example, studies of the murine RASGRF1 ortholog (Rasgrf1) show that it is predominantly expressed from the paternal allele in neonatal brain tissue, with expression becoming biallelic during weaning and later into adulthood (Plass et al, 1996;Drake et al, 2009). The spatio-temporal expression patterns of this gene have led to suggestions that it may play a role in memory and learning (Giese et al, 2001). Gene knockout studies have shown that mice strains deficient in Rasgrf1 activity display a moderate reduction in body weight (15% to 30%) compared to wild-type strains, suggesting a role for Rasgrf1 in post-natal growth and development (Giese et al, 2001;Clapcott et al, 2003;Drake et al, 2009).…”

Section: Snp Validation In Candidate Bovine Imprinted Genesmentioning

confidence: 99%

“…The spatio-temporal expression patterns of this gene have led to suggestions that it may play a role in memory and learning (Giese et al, 2001). Gene knockout studies have shown that mice strains deficient in Rasgrf1 activity display a moderate reduction in body weight (15% to 30%) compared to wild-type strains, suggesting a role for Rasgrf1 in post-natal growth and development (Giese et al, 2001;Clapcott et al, 2003;Drake et al, 2009). Interestingly, the differential Rasgrf1 gene expression levels in the mice models resulted in concordant differential expression of Igf1 (the insulin-like growth factor 1 gene) and molecular components of the growth hormone/insulin-like growth factor 1 (GH/IGF1) axis, which are essential for normal growth and development (Drake et al, 2009).…”

Section: Snp Validation In Candidate Bovine Imprinted Genesmentioning

confidence: 99%

A catalogue of validated single nucleotide polymorphisms in bovine orthologs of mammalian imprinted genes and associations with beef production traits

Magee

Berkowicz

Sikora

et al. 2010

Animal

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Genetic (or 'genomic') imprinting, a feature of approximately 100 mammalian genes, results in monoallelic expression from one of the two parentally inherited chromosomes. To date, most studies have been directed on imprinted genes in murine or human models; however, there is burgeoning interest in the effects of imprinted genes in domestic livestock species. In particular, attention has focused on imprinted genes that influence foetal growth and development and that are associated with several economically important production traits in cattle, sheep and pigs. We have re-sequenced regions in 20 candidate bovine imprinted genes in order to validate single nucleotide polymorphisms (SNPs) that may influence important production traits in cattle. Putative SNPs detected via re-sequencing were subsequently re-formatted for high-throughput SNP genotyping in 185 cattle samples comprising 138 performance-tested European Bos taurus (all Limousin bulls), 29 African B. taurus and 18 Indian B. indicus samples. Analysis of the resulting genotypic data identified 117 validated SNPs. Preliminary genotype-phenotype association analyses using 83 SNPs that were polymorphic in the Limousin samples with minor allele frequencies >0.05 revealed significant associations between two candidate bovine imprinted genes and a range of important beef production traits: average daily gain, average feed intake, live weight, feed conversion ratio, residual feed intake and residual gain. These genes were the Ras proteinspecific guanine nucleotide releasing factor gene ( RASGRF1) and the zinc finger, imprinted 2 gene ( ZIM2). Despite the relatively small sample size used in these analyses, the observed associations with production traits are supported by the purported biological function of the RASGRF1 and ZIM2 gene products. These results support the hypothesis that imprinted genes contribute significantly to important complex production traits in cattle. Furthermore, these SNPs may be usefully incorporated into future marker-assisted and genomic selection breeding schemes.

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Hippocampus-dependent learning and memory is impaired in mice lacking the Ras-guanine-nucleotide releasing factor 1 (Ras-GRF1)

Cited by 139 publications

References 44 publications

P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination

P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination

Molecular and cellular cognitive studies of the role of synaptic plasticity in memory

A catalogue of validated single nucleotide polymorphisms in bovine orthologs of mammalian imprinted genes and associations with beef production traits

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