Presynaptic type III neuregulin1-ErbB signaling targets<i>α</i>7 nicotinic acetylcholine receptors to axons

Hancock, Melissa L.; Canetta, Sarah; Role, Lorna W.; Talmage, David A.

doi:10.1085/jgp1316oia4

Cited by 8 publications

(5 citation statements)

References 1 publication

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“…NRG1 type III acts in a contact-dependant manner, is expressed higher in deeper cortical layers and can be found on axons of projection neurons. 39, 40 Furthermore, NRG1 type III is membrane bound and thought to be uniquely capable of back signaling to the nucleus by proteolytic processing and release of a transcriptionally active intracytoplasmic domain that increases neuronal survival. 41 We previously found evidence of increased NRG1-intracytoplasmic domain domain in the DLPFC of people with schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity

et al. 2012

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Excitement and controversy have followed neuregulin (NRG1) since its discovery as a putative schizophrenia susceptibility gene; however, the mechanism of action of the associated risk haplotype (HapICE) has not been identified, and specific genetic variations, which may increase risk to schizophrenia have remained elusive. Using a postmortem brain cohort from 37 schizophrenia cases and 37 controls, we resequenced upstream of the type I–IV promoters, and the HapICE repeat regions in intron 1. Relative abundance of seven NRG1 mRNA transcripts in the prefrontal cortex were determined and compared across diagnostic and genotypic groups. We identified 26 novel DNA variants and showed an increased novel variant load in cases compared with controls (χ2=7.815; P=0.05). The average nucleotide diversity (θ=10.0 × 10−4) was approximately twofold higher than that previously reported for BDNF, indicating that NRG1 may be particularly prone to genetic change. A greater nucleotide diversity was observed in the HapICE linkage disequilibrium block in schizophrenia cases (θ(case)=13.2 × 10−4; θ(control)=10.0 × 10−4). The specific HapICE risk haplotype was associated with increased type III mRNA (F=3.76, P=0.028), which in turn, was correlated with an earlier age of onset (r=−0.343, P=0.038). We found a novel intronic five-SNP haplotype ∼730 kb upstream of the type I promoter and determined that this region functions as transcriptional enhancer that is suppressed by SRY. We propose that the HapICE risk haplotype increases expression of the most brain-abundant form of NRG1, which in turn, elicits an earlier clinical presentation, thus providing a novel mechanism through which this genetic association may increase risk of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity

et al. 2012

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“…Interestingly, BACE1 has been found to regulate neuregulin-1 (NRG1) cleavage (Hu et al, 2006; Willem et al, 2006), and indeed this process is affected in BACE1 KOs (Savonenko et al, 2008). NRG1 is critically involved in maintaining surface expression of presynaptic α7-nAChRs (Hancock et al, 2008; Zhong et al, 2008). However, in isolated CA3 slices, we did not see a change in the total or cell surface levels of α7-nAChRs and NRG1 in the KOs (Supplementary Figure 3).…”

Section: Discussionmentioning

confidence: 99%

Mossy Fiber Long-Term Potentiation Deficits in BACE1 Knock-Outs Can Be Rescued by Activation of α7 Nicotinic Acetylcholine Receptors

Wang¹,

Lee²,

Lee³

et al. 2010

J. Neurosci.

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Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1)–the neuronal β-secretase responsible for producing β-amyloid (Aβ) peptides–emerged as one of the key therapeutic targets of Alzheimer's disease (AD). Although complete ablation of the BACE1 gene prevents Aβ formation, we reported that BACE1 knockout mice display severe presynaptic deficits at mossy fiber (MF) to CA3 synapses in the hippocampus, a major locus of BACE1 expression. We also found that the deficits are likely due to abnormal presynaptic Ca2+ regulation. Cholinergic system has been implicated in AD, in some cases involving Ca2+-permeable α7-nicotinic acetylcholine receptors (nAChRs). Here we report that brief application of nicotine, via α7-nAChRs, can restore mossy fiber LTP (mfLTP) in BACE1 knockouts. Our data suggest that activating α7-nAChRs can recover the presynaptic deficits in BACE1 knockouts.

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“…Neuregulin 1 (Nrg1) is a member of the epidermal growth factor family and functions through the activation of the tyrosine kinase domain of ErbB receptors ( 1 ). The bioactivity of Nrg1 is primarily mediated via homodimers consisting of its cognate receptor ErbB4 ( 2 ) or via heterodimeric complexes of ErbB3⁄Neu and ErbB4⁄Neu ( 3 ). These receptors, including Neu and ErbB4, have a high affinity for Nrg1 and contain an active tyrosine kinase domain ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Differential changes in Neuregulin-1 signaling in major brain regions in a lipopolysaccharide-induced neuroinflammation mouse model

Zhai

Jiang

Chen

et al. 2016

Molecular Medicine Reports

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Neuregulin 1 (Nrg1) is involved in multiple biological processes in the nervous system. The present study investigated changes in Nrg1 signaling in the major brain regions of mice subjected to lipopolysaccharide (LPS)-induced neuroinflammation. At 24 h post-intraperitoneal injection of LPS, mouse brain tissues, including tissues from the cortex, striatum, hippocampus and hypothalamus, were collected. Reverse transcription-polymerase chain reaction was used to determine the expression of Nrg1 and its receptors, Neu and ErbB4, at the mRNA level. Western blotting was performed to determine the levels of these proteins and the protein levels of phosphorylated extracellular signal-regulated kinases (Erk)1/2 and Akt1. Immunohistochemical staining was utilized to detect the levels of pNeu and pErbB4 in these regions. LPS successfully induced sites of neuroinflammation in these regions, in which changes in Nrg1, Neu and ErbB4 at the mRNA and protein levels were identified compared with controls. LPS induced a reduction in pNeu and pErbB4 in the striatum and hypothalamus, although marginally increased pErbB4 levels were found in the hippocampus. LPS increased the overall phosphorylation of Src but this effect was reduced in the hypothalamus. Moreover, increased phosphorylation of Akt1 was found in the striatum and hippocampus. These data suggest diverse roles for Nrg1 signaling in these regions during the process of neuroinflammation.

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Presynaptic type III neuregulin1-ErbB signaling targetsα7 nicotinic acetylcholine receptors to axons

Cited by 8 publications

References 1 publication

Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity

Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity

Mossy Fiber Long-Term Potentiation Deficits in BACE1 Knock-Outs Can Be Rescued by Activation of α7 Nicotinic Acetylcholine Receptors

Differential changes in Neuregulin-1 signaling in major brain regions in a lipopolysaccharide-induced neuroinflammation mouse model

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