SOS1-/- mice impair Cdc42 activation in PC12 cells.
1: Mol Biol Cell. 2005 May;16(5):2207-17. Epub 2005 Feb 23.
Local phosphatidylinositol 3,4,5-trisphosphate accumulation recruits Vav2 and
Vav3 to activate Rac1/Cdc42 and initiate neurite outgrowth in nerve growth
factor-stimulated PC12 cells.
Aoki K, Nakamura T, Fujikawa K, Matsuda M.
Department of Tumor Virology, Research Institute for Microbial Diseases, Osaka
University, Osaka 565-0871, Japan.
Neurite outgrowth is an important process in the formation of neuronal networks.
Rac1 and Cdc42, members of the Rho-family GTPases, positively regulate neurite
extension through reorganization of the actin cytoskeleton. Here, we examine the
dynamic linkage between Rac1/Cdc42 and phosphatidylinositol 3-kinase
(PI3-kinase) during nerve growth factor (NGF)-induced neurite outgrowth in PC12
cells. Activity imaging using fluorescence resonance energy transfer probes
showed that PI3-kinase as well as Rac1/Cdc42 was transiently activated in broad
areas of the cell periphery immediately after NGF addition. Subsequently, local
and repetitive activation of PI3-kinase and Rac1/Cdc42 was observed at the
protruding sites. Depletion of Vav2 and Vav3 by RNA interference significantly
inhibited both Rac1/Cdc42 activation and the formation of short processes
leading to neurite outgrowth. At the NGF-induced protrusions, local
phosphatidylinositol 3,4,5-trisphosphate accumulation recruited Vav2 and Vav3 to
activate Rac1 and Cdc42, and conversely, Vav2 and Vav3 were required for the
local activation of PI3-kinase. These observations demonstrated for the first
time that Vav2 and Vav3 are essential constituents of the positive feedback loop
that is comprised of PI3-kinase and Rac1/Cdc42 and cycles locally with
morphological changes.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 15728722 [PubMed - indexed for MEDLINE]
SOS-/- fly impair the development of eyes.
1: Cell. 1991 Jan 11;64(1):39-48.
Genetic dissection of a neurodevelopmental pathway: Son of sevenless functions
downstream of the sevenless and EGF receptor tyrosine kinases.
Rogge RD, Karlovich CA, Banerjee U.
Department of Biology, University of California, Los Angeles 90024.
We have isolated a dominant mutation in a gene called Son of sevenless (Sos)
that is an allele-specific suppressor of the sevenless phenotype. This
suppressor function is autonomously required in R7 and is sensitive to the
dosage of the Sos and bride of sevenless genes. Loss-of-function alleles of Sos
are recessive lethals, but in the eye Sos has a role in R cell development.
Mutations in Sos also interact with the Ellipse allele of the Drosophila EGF
receptor. We propose a model suggesting that the Sos product is downstream of
sevenless and the EGF receptor, and that the dominant suppression results from
the overexpression or increased activity of the gene product.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
PMID: 1846090 [PubMed - indexed for MEDLINE]
Overexpression of GAB1 exhibit neurite outgrowth, DNA synthesis and survival in PC12 cells.
1: J Biol Chem. 1999 Dec 24;274(52):37307-14.
Gab1 mediates neurite outgrowth, DNA synthesis, and survival in PC12 cells.
Korhonen JM, Said FA, Wong AJ, Kaplan DR.
Montreal Neurological Institute, Brain Tumor Research Centre, Montreal, Quebec
H3A 2B4, Canada.
The Gab1-docking protein has been shown to regulate phosphatidylinositol
3-kinase PI3K activity and potentiate nerve growth factor (NGF)-induced survival
in PC12 cells. Here, we investigated the potential of Gab1 to induce neurite
outgrowth and DNA synthesis, two other important aspects of NGF-induced neuronal
differentiation of PC12 cells and NGF-independent survival. We generated a
recombinant adenovirus encoding hemagglutinin (HA)-epitope-tagged Gab1 and
expressed this protein in PC12 cells. HA-Gab1 was constitutively
tyrosine-phosphorylated in PC12 cells and induced the phosphorylation of
Akt/protein kinase B and p44/42 mitogen-activated protein kinase.
HA-Gab1-stimulated a 10-fold increase in neurite outgrowth in the absence of NGF
and a 5-fold increase in NGF-induced neurite outgrowth. HA-Gab1 also stimulated
DNA synthesis and caused NGF-independent survival in PC12 cells. Finally, we
found that HA-Gab1-induced neuritogenesis was completely suppressed by
pharmacological inhibition of mitogen-activated protein kinase kinase (MEK)
activity and 50% suppressed by inhibition of PI3K activity. In contrast,
HA-Gab1-stimulated cell survival was efficiently suppressed only by inhibition
of both PI3K and MEK activities. These results indicate that Gab1 is capable of
mediating differentiation, DNA synthesis, and cell survival and uses both PI3K
and MEK signaling pathways to achieve its effects.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 10601297 [PubMed - indexed for MEDLINE]
SHCB-deficient animals exhibit a loss of peptidergic and nonpeptidergic nociceptive sensory neurons,
1: Neuron. 2000 Dec;28(3):819-33.
The mammalian ShcB and ShcC phosphotyrosine docking proteins function in the
maturation of sensory and sympathetic neurons.
Sakai R, Henderson JT, O'Bryan JP, Elia AJ, Saxton TM, Pawson T.
Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute,
Mount Sinai Hospital, 600 University Avenue, M5G 1X5, Toronto, Ontario, Canada.
Shc proteins possess SH2 and PTB domains and serve a scaffolding function in
signaling by a variety of receptor tyrosine kinases. There are three known
mammalian Shc genes, of which ShcB and ShcC are primarily expressed in the
nervous system. We have generated null mutations in ShcB and ShcC and have
obtained mice lacking either ShcB or ShcC or both gene products. ShcB-deficient
animals exhibit a loss of peptidergic and nonpeptidergic nociceptive sensory
neurons, which is not enhanced by additional loss of ShcC. Mice lacking both
ShcB and ShcC exhibit a significant loss of neurons within the superior cervical
ganglia, which is not observed in either mutant alone. The results indicate that
these Shc family members possess both unique and overlapping functions in
regulating neural development and suggest physiological roles for ShcB/ShcC in
TrkA signaling.
PMID: 11163269 [PubMed - indexed for MEDLINE]
Hippocampal long-term potentiation in ShcC mutant mice is significantly enhanced.
1: J Neurosci. 2005 Feb 16;25(7):1826-35.
Hippocampal synaptic modulation by the phosphotyrosine adapter protein
ShcC/N-Shc via interaction with the NMDA receptor.
Miyamoto Y, Chen L, Sato M, Sokabe M, Nabeshima T, Pawson T, Sakai R, Mori N.
Department of Molecular Genetics, National Institute for Longevity Sciences,
Oobu 474-8522, Japan.
N-Shc (neural Shc) (also ShcC), an adapter protein possessing two
phosphotyrosine binding motifs [PTB (phosphotyrosine binding) and SH2 (Src
homology 2) domains], is predominantly expressed in mature neurons of the CNS
and transmits neurotrophin signals from the TrkB receptor to the
Ras/mitogen-activated protein kinase (MAPK) pathway, leading to cellular growth,
differentiation, or survival. Here, we demonstrate a novel role of ShcC, the
modulation of NMDA receptor function in the hippocampus, using ShcC
gene-deficient mice. In behavioral analyses such as the Morris water maze,
contextual fear conditioning, and novel object recognition tasks, ShcC mutant
mice exhibited superior ability in hippocampus-dependent spatial and nonspatial
learning and memory. Consistent with this finding, electrophysiological analyses
revealed that hippocampal long-term potentiation in ShcC mutant mice was
significantly enhanced, with no alteration of presynaptic function, and the
effect of an NMDA receptor antagonist on its expression in the mutant mice was
notably attenuated. The tyrosine phosphorylation of NMDA receptor subunits NR2A
and NR2B was also increased, suggesting that ShcC mutant mice have enhanced NMDA
receptor function in the hippocampus. These results indicate that ShcC not only
mediates TrkB-Ras/MAPK signaling but also is involved in the regulation of NMDA
receptor function in the hippocampus via interaction with phosphotyrosine
residues on the receptor subunits and serves as a modulator of hippocampal
synaptic plasticity underlying learning and memory.
PMID: 15716419 [PubMed - indexed for MEDLINE]
SHCA controls the size of brain.
1: J Neurosci. 2006 Jul 26;26(30):7885-97.
Neural-specific inactivation of ShcA results in increased embryonic neural
progenitor apoptosis and microencephaly.
McFarland KN, Wilkes SR, Koss SE, Ravichandran KS, Mandell JW.
Department of Pathology (Neuropathology), Beirne B. Carter Center for Immunology
Research, University of Virginia, Charlottesville, Virginia 22908, USA.
Brain size is precisely regulated during development and involves coordination
of neural progenitor cell proliferation, differentiation, and survival. The
adapter protein ShcA transmits signals from receptor tyrosine kinases via MAPK
(mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase)
and PI3K (phosphatidylinositol 3-kinase)/Akt signaling pathways. In the CNS,
ShcA expression is high during embryonic development but diminishes as cells
differentiate and switches to ShcB/Sck/Sli and ShcC/N-Shc/Rai. To directly test
ShcA function in brain development, we used Cre/lox technology to express a
dominant-negative form of ShcA (ShcFFF) in nestin-expressing neural progenitors.
ShcFFF-expressing mice display microencephaly with brain weights reduced to 50%
of littermate controls throughout postnatal and adult life. The cerebrum
appeared most severely affected, but the gross architecture of the brain is
normal. Body weight was mildly affected with a delay in reaching mature weight.
At a mechanistic level, the ShcFFF microencephaly phenotype appears to be
primarily attributable to elevated apoptosis levels throughout the brain from
embryonic day 10.5 (E10.5) to E12, which declined by E14.5. Apoptosis remained
at normal basal levels throughout postnatal development. Proliferation indices
were not significantly altered in the embryonic neuroepithelium or within the
postnatal subventricular zone. In another approach with the same nestin-Cre
transgene, conditional deletion of ShcA in mice with a homozygous floxed shc1
locus also showed a similar microencephaly phenotype. Together, these data
suggest a critical role for ShcA in neural progenitor survival signaling and in
regulating brain size.
PMID: 16870734 [PubMed - indexed for MEDLINE]
Cbl-b null mice exhibit the enhancement of long-term memory.
1: Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5125-30. Epub 2006 Mar 20.
Enhancement of long-term memory retention and short-term synaptic plasticity in
cbl-b null mice.
Tan DP, Liu QY, Koshiya N, Gu H, Alkon D.
Blanchette Rockefeller Neurosciences Institute, Rockville, MD 20850, USA.
[email protected]
The cbl-b gene is a member of the cbl protooncogene family. It encodes a protein
with multiple domains, which can interact with other proteins in a variety of
signaling pathways. The functions of cbl family genes in the brain are unknown.
In this report, we used genetic, immunohistochemical, behavioral, and
electrophysiological approaches to study the role of cbl-b in learning and
memory. Cbl-b null mice developed normally and had no abnormalities in their
locomotor performance. In spatial learning and memory studies, cbl-b null and WT
mice performed similarly during training. To test memory retention, two probe
trials were used. cbl-b null mice performed slightly better 1 day after
training. However, in the probe trial 45 days after training, the cbl-b null
group showed significantly higher memory retention than WT mice, suggesting an
enhancement of long-term memory. Using electrophysiological approaches, we found
there was enhanced paired-pulse facilitation in the Schaffer Collateral-CA1
glutamatergic synapses of the cbl-b null mice. On the other hand, there was no
difference in long-term potentiation between the two groups of mice. In summary,
we provide evidence that (i) cbl-b protein is concentrated in the synaptic
regions of CA1, CA3, and the dentate gyrus of the hippocampus; (ii) cbl-b null
mice have enhanced long-term memory; and (iii) cbl-b null mice show an
enhancement in short-term plasticity. These results indicate that cbl-b is a
negative regulator of long-term memory, and its neuronal mechanism regulates
synaptic transmission in the hippocampus.
PMID: 16549761 [PubMed - indexed for MEDLINE]
最終更新：2006年12月14日 21:35
