Shared and Unique Roles of Cap23 and Gap43 in Actin Regulation, Neurite Outgrowth, and Anatomical Plasticity

Frey, Dunja; Laux, Thorsten; Xu, Linfeng; Schneider, Corinna; Caroni, Pico

doi:10.1083/jcb.149.7.1443

Cited by 252 publications

(221 citation statements)

References 33 publications

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“…Both proteins play a critical role in regulating neuritic outgrowth as well as the actin cytoskeleton and BASP1 can functionally substitute for GAP-43 in vivo. 64 Our results for BASP1 expression complement recent findings by Prabakaran et al 16 who also demonstrated a > 2-fold increase in BASP1 expression in the white matter of schizophrenic brains. Interestingly, reductions in GAP-43 gene and protein expression have been reported in the SCZ and BPD brain.…”

Section: Discussionsupporting

confidence: 90%

“…63 It is a cytoskeleton-associated, calmodulin-binding protein that is widely and abundantly expressed during brain development, maintained in selected brain structures in the adult and reinduced during nerve regeneration. 64 BASP1 is functionally related to GAP-43. Both proteins play a critical role in regulating neuritic outgrowth as well as the actin cytoskeleton and BASP1 can functionally substitute for GAP-43 in vivo.…”

Section: Discussionmentioning

confidence: 99%

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Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression

et al. 2008

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The dorsolateral prefrontal cortex (dlpfc) is strongly implicated in the pathogenesis of schizophrenia (SCZ) and bipolar disorder (BPD) and, within this region, abnormalities in glutamatergic neurotransmission and synaptic function have been described. Proteins associated with these functions are enriched in membrane microdomains (MM). In the current study, we used two complementary proteomic methods, two-dimensional difference gel electrophoresis and one-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis followed by reverse phase-liquid chromatography-tandem mass spectrometry (RP-LC-MS/MS) (gel separation liquid chromatography-tandem mass spectrometry (GeLC-MS/MS)) to assess protein expression in MM in pooled samples of dlpfc from SCZ, BPD and control cases (n = 10 per group) from the Stanley Foundation Brain series. We identified 16 proteins altered in one/both disorders using proteomic methods. We selected three proteins with roles in synaptic function (syntaxin-binding protein 1 (STXBP1), brain abundant membrane-attached signal protein 1 (BASP1) and limbic system-associated membrane protein (LAMP)) for validation by western blotting. This revealed significantly increased expression of these proteins in SCZ (STXBP1 (24% difference; P < 0.001), BASP1 (40% difference; P < 0.05) and LAMP (22% difference; P < 0.01)) and BPD (STXBP1 (31% difference; P < 0.001), BASP1 (23% difference; P < 0.01) and LAMP (20% difference; P < 0.01)) in the Stanley brain series (n = 20 per group). Further validation in dlpfc from the Harvard brain subseries (n = 10 per group) confirmed increased protein expression in SCZ of STXBP1 (18% difference; P < 0.0001), BASP1 (14% difference; P < 0.0001) but not LAMP (20% difference; P = 0.14). No significant differences in STXBP1, BASP1 or LAMP protein expression in BPD dlpfc were observed. This study, through proteomic assessments of MM in dlpfc and validation in two brain series, strongly implicates LAMP, STXBP1 and BASP1 in SCZ and supports the view of a neuritic and synaptic dysfunction in the neuropathology of SCZ.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression

et al. 2008

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“…Indeed, strong ANX2 immunoreactivity was found in the growth cones, as identified by its morphology and GAP43 staining (Fig. 5a), a growth cone enriched protein (Skene 1989;Frey et al 2000). ANX2 also co-localized with TUC-4 (Fig.…”

Section: Anx2 Is Concentrated In Growth Cones and Cultured Neuronal Tmentioning

confidence: 89%

Expression of annexin A2 in GABAergic interneurons in the normal rat brain

Zhao

2006

Journal of Neurochemistry

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Expression of the Ca 2+ -dependent phospholipids binding protein annexin A2 (ANX2) in the brain is thought to be largely associated with brain pathological conditions such as tumor, inflammation, and neurodegeneration. The recent findings that ANX2 heterotetramer is involved in learning and neuronal activities necessitates a systematic investigation of the physiological expression of ANX2 in the brain. With combination of in situ hybridization and immunohistochemistry, ANX2 mRNA and protein were specifically detected in a group of GABAergic interneurons throughout the brain. Although ANX2 was absent from the interior of pyramidal neurons, it was found on the membrane and seemly the extracellular space of those neurons, where they closely co-localized with glutamate decarboxylase terminals. In cultured developing neurons, ANX2 was present at high concentrations in the growth cones co-distributing with several growth-associated proteins such as growth associated protein 43 (GAP43), turned on after division/Ulip/CRMP (TUC-4), tubulin, and tissue-plasminogen activator. It then became predominantly distributed on the membrane and mostly in axonal branches as neurons grew and extended synaptic networks. ANX2 was also secreted from cultured neurons, in a membrane-bound form that was Ca 2+ -dependent, which was significantly increased by neuronal depolarization. These results may have implications in the function and regulatory mechanism of ANX2 in the normal brain.

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“…20 GAP-43 also plays a role in sprouting responses associated with adult plasticity. 21 GAP-43 is expressed along with BDNF in response to neuronal injuries and is upregulated in granule cells following BDNF treatment. 22,23 In the present study, we test whether GAP-43 is an essential downstream effector of positive AMPA receptor modulators and subsequent BDNF-induced responses.…”

mentioning

confidence: 99%

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

et al. 2009

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Positive a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators include benzamide compounds that allosterically modulate AMPA glutamate receptors. These small molecules that cross the blood-brain barrier have been shown to act as a neuroprotectant by increasing the levels of endogenous brain-derived neurotrophic factor (BDNF). Positive AMPA receptor modulators have also been shown to increase the levels of growth-associated protein-43 (GAP-43). GAP-43 plays a major role in many aspects of neuronal function in vertebrates. The goal of this study was to determine whether GAP-43 was important in mediating the actions of positive AMPA receptor modulator (S18986) and BDNF. Using cortical cultures from GAP-43 knockout and control mice, we show that (1) GAP-43 is upregulated in response to S18986 and BDNF in control cultures; (2) this upregulation of GAP-43 is essential for mediating the neuroprotective effects of S18986 and BDNF; (3) administration of S18986 and BDNF leads to an increase in the expression of the glutamate transporters GLT-1 and GLAST that are key to limiting excitotoxic cell death and this increase in GLT-1 and GLAST expression is completely blocked in the absence of GAP-43. Taken together this study concludes that GAP-43 is an important mediator of the neurotrophic effects of S18986 and BDNF on neuronal survival and plasticity, and is essential for the success of positive AMPA receptor modulator-BDNF-based neurotrophin therapy. Positive a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators allosterically modulate AMPA-type glutamate receptors and facilitate fast excitatory transmission, 1,2 and have been shown to enhance learning and memory. [3][4][5] Positive AMPA receptor modulators also decrease neuronal loss in excitotoxic neonatal brain lesions. 6 Thus, positive AMPA receptor modulators are potential candidates for treatment of diseases characterized by cognitive dysfunction and neuronal loss. 7,8 Some of the effects of positive AMPA receptor modulators are mediated via increased BDNF expression. 9,10 Positive AMPA receptor modulators however are preferred over direct administration of BDNF itself as this class of molecules readily crosses the blood-brain barrier. 11 Brain-derived neurotrophic factor is important for appropriate development and connectivity of neurons as well as their survival. 12,13 In adults, activity dependent modulation of BDNF levels is important for synaptic plasticity and remodeling. 14,15 Activation of the extracellular-regulated kinases (ERKs) pathway by BDNF is important for neuronal survival. 16,17 BDNF mediates activity dependent synaptic plasticity by mechanisms that involve receptor regulation and localized gene transcription. 18,19 At present, it is unclear whether the neuroprotection, synaptic remodeling and plasticity effects of BDNF are related to each other through common downstream elements.Growth-associated protein-43 (GAP-43) is a nervous system specific F-actin regulating phosphoprotein expressed during de...

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Shared and Unique Roles of Cap23 and Gap43 in Actin Regulation, Neurite Outgrowth, and Anatomical Plasticity

Cited by 252 publications

References 33 publications

Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression

Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression

Expression of annexin A2 in GABAergic interneurons in the normal rat brain

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

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