Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos

Bao, Jianxin; Lin, Hai; Ouyang, Yanling; Lei, Debin; Osman, Abdullah A.; Kim, Tae Wan; Mei, Lin; Dai, Peng; Ohlemiller, Kevin K.; Ambron, Richard T.

doi:10.1038/nn1342

Cited by 153 publications

(154 citation statements)

References 49 publications

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“…Among the samples, we detected NRG1 immunoreactive bands ranging from 23-130kDa, which were preabsorbable with the NRG1 peptide but not with an unrelated peptide ( Figure 2A). Based on NRG1 molecular weights reported previously, we speculate that the 88-130kDa immunoreactive bands represent full-length NRG1 (Frenzel and Falls 2001;Hahn et al 2006;Law et al 2004) while the 48-59kDa immunoreactive bands correspond to cleaved NRG1 intracellular fragments (Bao et al 2004;Carroll et al 1997;Frenzel and Falls 2001;Hahn et al 2006;Law et al 2004). The smaller immunoreactive bands ranging from 23-42kDa have not been documented in neuronal tissue/cells, but are comparable to NRG1 molecular weights observed in peripheral tissue (Cote et al 2005;Hirata et al 2007;Lebrasseur et al 2003).…”

Section: Detected Nrg1 and Erbb4 Immunoreactive Bandsmentioning

confidence: 58%

“…Furthermore, the 53kDa fragment detected by the antibody we used has been functionally characterized as the NRG1-ICD (Bao et al 2003;Bao et al 2004;Wang et al 1998). Only the 53kDa NRG1 protein was found to be significantly affected by diagnosis specifically in PFC cytoplasmic fractions [ANOVA: F(3,53)=5.94, p=0.001; Table 2; Figure 3].…”

Section: Nrg1 Intracellular Cleavage Domain (Nrg1-icd) Protein Levelsmentioning

confidence: 99%

“…Since full-length and cleaved NRG1 and ErbB4 can have unique functions in the cytoplasm and in the nucleus (Bao et al 2003;Bao et al 2004;Garcia et al 2000;Hahn et al 2006;Sardi et al 2006;Wang et al 1998), the levels of NRG1 and ErbB4 proteins, along with their cleavage products, may vary in mental illness according to intracellular compartment. Therefore, we examined the quantities of NRG1 and ErbB4 proteins, along with their possible cleavage products, in PFC cytoplasmic and nuclear fractions.…”

Section: Introductionmentioning

confidence: 99%

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Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients

Chong

Thompson

Beltaifa

et al. 2008

Schizophrenia Research

168

126

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Neuregulin-1 (NRG1) and its receptor, ErbB4, have been implicated in schizophrenia at both gene and transcript levels. The present investigation compared NRG1 and ErbB4 protein levels in prefrontal cortical (PFC) cytoplasmic and nuclear fractions among normal, schizophrenic, bipolar and major depressed subjects from the Stanley Consortium. We used immunoblotting procedures to examine potential NRG1 and ErbB4 immunoreactive bands, but specifically quantified NRG1 immunoreactive signals at 42, 48 and 53kDa and ErbB4 immunoreactive signals at 21, 55, 60 and 180kDa. PFC cytoplasmic 53kDa NRG1 protein levels were significantly increased (~20%) in schizophrenic patients relative to each of the other subject groups. We also detected a trend towards diagnostic effects on PFC cytoplasmic full-length (180kDa) ErbB4 protein levels, and post hoc tests revealed that these quantities were significantly increased (~30%) in schizophrenic patients relative to normal and to depressed subjects. In addition, we examined the levels of potential ErbB4 cleavage products at 21, 55 and 60kDa relative to those of full-length ErbB4 in the PFC fractions. We detected trends for diagnostic effects on PFC cytoplasmic 21kDa/180kDa and 55kDa/180kDa ratios, and post hoc tests revealed that these ratios were significantly reduced in schizophrenic patients relative to normal individuals. Our investigation suggests that schizophrenia-associated NRG1 and ErbB4 mRNA elevations also occur at the protein level and may be specific to schizophrenia. We hypothesize that ErbB4 proteolytic processing may also be altered in schizophrenia, yielding altered ratios of functionally distinct forms of ErbB4.

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Section: Detected Nrg1 and Erbb4 Immunoreactive Bandsmentioning

confidence: 58%

Section: Nrg1 Intracellular Cleavage Domain (Nrg1-icd) Protein Levelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients

Chong

Thompson

Beltaifa

et al. 2008

Schizophrenia Research

168

126

View full text Add to dashboard Cite

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“…A cytoplasmic fragment is released, that can translocate into the nucleus and influence transcription (Bao et al, 2004). TACE/ADAM17 cleaves NRG1 in the exon "1" a few aminoacids (3-6) upstream the cleavage site of BACE-1 (La Marca et al, 2011) and its down-regulation leads to precocious-and hypermyelination, that is neuron-autonomous (indeed, TACE inactivation in SC does not alter myelination).…”

Section: Nrg1 Cleavage and Consequences On Myelination Activitymentioning

confidence: 99%

“…BACE-1 cleavage stimulates myelination (Hu et al, 2006;Willem et al, 2006) and remyelination (Hu et al, 2008), TACE cleavage inhibits myelination (La Marca et al, 2011) . A second cleavage by a γ-secretase dependent protease, in those NRG1 isoforms containing the TMc, generates a cytoplasmic fragment that can translocate into the nucleus and influence gene transcription (Bao et al, 2004).…”

mentioning

confidence: 99%

Neuregulin 1 Role in Schwann Cell Regulation and Potential Applications to Promote Peripheral Nerve Regeneration

Gambarotta

Fregnan

Gnavi

et al. 2013

International Review of Neurobiology

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Neuregulin 1 (NRG1) is a multifunctional and versatile protein: its numerous isoforms can signal in a paracrine, autocrine or juxtacrine manner, playing a fundamental role during the development of the peripheral nervous system and during the process of nerve repair, suggesting that the treatment with NRG1 could improve functional outcome following injury. Accordingly, the use of NRG1 in vivo has already yielded encouraging results.The aim of this review is to focus on the role played by the different NRG1 isoforms during peripheral nerve regeneration and remyelination and to identify good candidates to be used for the development of tissue engineered medical devices delivering NRG1, with the final goal to promote better nerve repair.

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Biological Validation of Increased Schizophrenia Risk With NRG1, ERBB4, and AKT1 Epistasis via Functional Neuroimaging in Healthy Controls

Nicodemus¹,

Law²,

Radulescu³

et al. 2010

Arch Gen Psychiatry

117

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CONTEXT NRG1 is a schizophrenia candidate gene and plays an important role in brain development and neural function. Schizophrenia is a complex disorder, with etiology likely due to epistasis. OBJECTIVE We sought to examine epistasis between NRG1 and selected NMDA-glutamate pathway partners implicated in its effects, including ERBB4, AKT1, DLG4, NOS1, NOS1AP. DESIGN Schizophrenia case-control sample analyzed using machine learning algorithms and logistic regression with follow-up using neuroimaging on an independent sample of healthy controls. PARTICIPANTS A referred sample of schizophrenic patients (N = 296) meeting DSM-IV criteria for schizophrenia-spectrum disorder and a volunteer sample of controls for case-control comparison (N = 365) and a separate volunteer sample of controls for neuroimaging (N = 172). MAIN OUTCOME MEASURES Epistatic association between SNPs and case-control status; epistatic association between SNPs and the BOLD physiological response during working memory measured by functional magnetic resonance imaging (fMRI). RESULTS We observed interaction between NRG1 5’ and 3’ SNPs: rs4560751-rs3802160 (likelihood ratio test (LRT) p=0.00020) and schizophrenia which was validated using fMRI of working memory in healthy controls; carriers of risk-associated genotypes showed inefficient processing in dorsolateral prefrontal cortex (DLPFC) (p=0.015, FWE corrected). We observed epistasis between NRG1 (rs10503929; Val1066Ile) and its receptor ERBB4 (rs1026882; LRT p=0.035); a three-way interaction with these two SNPs and AKT1 (rs2494734) was also observed (OR=27.13; 95% confidence interval 3.30, 223.03; LRT p=0.042). These same two- and three-way interactions were further biologically validated via fMRI: healthy individuals carrying risk genotypes for NRG1 and ERBB4, or these two together with AKT1, were disproportionately less efficient in DLPFC processing. Lower-level interactions were not observed between NRG1/ERBB4-AKT1 in association or neuroimaging, consistent with biological evidence that NRG1-ERBB4 interaction modulates downstream AKT1 signaling. CONCLUSIONS Our data suggest complex epistatic effects implicating a NRG1 molecular pathway in cognitive brain function and the pathogenesis of schizophrenia.

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Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos

Cited by 153 publications

References 49 publications

Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients

Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients

Neuregulin 1 Role in Schwann Cell Regulation and Potential Applications to Promote Peripheral Nerve Regeneration

Biological Validation of Increased Schizophrenia Risk With NRG1, ERBB4, and AKT1 Epistasis via Functional Neuroimaging in Healthy Controls

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