Neuregulin-1 alpha, the underestimated molecule: emerging new roles in normal brain function and the pathophysiology of schizophrenia?

Bernstein, Hans‐Gert; Bogerts, Bernhard

doi:10.1139/gen-2013-0171

Cited by 4 publications

(5 citation statements)

References 16 publications

(17 reference statements)

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“…Nrg1α-induced activation of PI3K signaling is also impaired in lymphoblastoid cell lines derived from schizophrenia patients (Law et al, 2012). This suggests Nrg1α plays important roles in both normal brain development and in schizophrenia etiology (Bernstein and Bogerts, 2013), and Nrg1α signaling may be disrupted in schizophrenia in a manner similar to that described in the present study.…”

Section: Discussionsupporting

confidence: 78%

“…We utilized a soluble form of the EGF-like domain of Nrg1α to stimulate Nrg/ErbB signaling. To date, the majority of research concerning the role of Nrg1 in neurons has focused on Nrg1β, leaving the α form largely unstudied (Bernstein and Bogerts, 2013). Nrg1α is highly expressed in pyramidal neurons and interneurons of the cortex and hippocampus of the human pre- and perinatal brain (Bernstein et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of the Schizophrenia-Associated MicroRNA miR-137 Disrupts Nrg1α Neurodevelopmental Signal Transduction

et al. 2017

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Summary Genomic studies have repeatedly associated variants in the gene encoding microRNA miR-137 with increased schizophrenia risk. Bioinformatic predictions suggest that miR-137 regulates schizophrenia-associated signaling pathways critical to neural development, but these predictions remain largely unvalidated. In the present study, we demonstrate that miR-137 regulates neuronal levels of p55γ, PTEN, Akt2, GSK3β, mTOR, and rictor. All are key proteins within the PI3K-Akt-mTOR pathway and act downstream of neuregulin (Nrg)/ErbB and BDNF signaling. Inhibition of miR-137 ablates Nrg1α-induced increases in dendritic protein synthesis, phosphorylated S6, AMPA receptor subunits, and outgrowth. Inhibition of miR-137 also blocks mTORC1-dependent responses to BDNF, including increased mRNA translation and dendritic outgrowth, while leaving mTORC1-independent S6 phosphorylation intact. We conclude that miR-137 regulates neuronal responses to Nrg1α and BDNF through convergent mechanisms, which might contribute to schizophrenia risk by altering neural development.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Inhibition of the Schizophrenia-Associated MicroRNA miR-137 Disrupts Nrg1α Neurodevelopmental Signal Transduction

et al. 2017

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“…The importance of CAMs in learning and memory‐associated disorders is also demonstrated in genome‐wide association studies (GWAS) data . Genetic variants of CAM genes have been associated with autism; variants in neuregulin ( NRG1 ) have been associated with vulnerability to schizophrenia; and variants in KIAA0319 have been associated with dyslexia …”

Section: Introductionmentioning

confidence: 95%

“…17,[19][20][21][22] The importance of CAMs in learning and memory-associated disorders is also demonstrated in genome-wide association studies (GWAS) data. 23,24 Genetic variants of CAM genes have been associated with autism; 9,25,26 variants in neuregulin (NRG1) have been associated with vulnerability to schizophrenia; 27,28 and variants in KIAA0319 have been associated with dyslexia. [29][30][31] Despite the importance of CAMs in normal physiology and in disorders of brain and other organs, there remains only a modest amount of updated, systematic work that (1) enumerates the genes and gene families that function as CAMs; (2) delineates those more likely to function in proper development, modulation, and maintenance of morphologically visible sites for physical interactions between cells and between cells and matrix (versus CAMs that appear to largely transmit information about cell-cell and cell-matrix interactions); (3) establishes the ways in which the patterns of CAM expression by any specific cell type might relate to the cells' connectivities and functions; (4) documents the ways in which CAM variation, taken as a whole, might relate to individual differences in vulnerabilities to disease; and (5) explores the ways in which CAM expression by specific cell types might relate to disease vulnerabilities.…”

Section: Introductionmentioning

confidence: 99%

Human cell adhesion molecules: annotated functional subtypes and overrepresentation of addiction‐associated genes

Zhong

Drgonová

et al. 2015

Annals of the New York Academy of Sciences

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Human cell adhesion molecules (CAMs) are essential both for a) proper development, modulation and maintenance of interactions between cells and for b) cell-to-cell (and matrix-to-cell) communication about these interactions. CAMs are thus key to proper development and plasticity of organs and tissues that include the brain. Despite recognition of the existence of these dual CAM roles and appreciation of the differential functional significance of these roles, there have been surprisingly few systematic studies that have carefully enumerated the universe of CAMs, identified the preferred roles for specific CAMs in distinct types of cellular connections and communication, or related these issues to specific brain disorders or brain circuits. In this paper, we substantially update and review the set of human genes that are likely to encode CAMs based on searches of databases, literature reviews and annotations. We describe the likely CAMs and the functional CAM subclasses into which they fall. These include “iCAMs”, whose contacts largely mediate cell to cell communication, those involved in focal adhesions, CAM genes whose products are preferentially involved with stereotyped and morphologically-identifiable connections between cells (adherens junctions, gap junctions) and smaller numbers of genes in other classes. We discuss a novel proposed mechanism involving selective anchoring of the constituents of iCAM-containing lipid rafts in zones of close neuronal apposition to membranes expressing binding partners of these iCAMs. CAM data from genetic and genomic studies of addiction in humans and mouse models provide examples of the ways in which CAM variation is likely to contribute to a specific brain-based disorder. We discuss how differences in CAM splicing mediated by differences in the addiction-associated splicing regulator RBFOX1/A2BP1 could enrich this picture. CAM expression in dopamine neurons provides one of the ways in which variations in cell adhesion molecule genes could impact a specific set of circuits central to addiction and drug reward.

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“…As GWAS and next generation sequencing (NGS) have rapidly developed recently, many gene loci have been associated with different neuropsychiatric disorders [8]. For instance, numerous genetic variants have been associated with SZ [9][10][11][12][13] and ASD [14][15][16][17]. Furthermore, a significant genetic correlation exists between ASD and SZ [17,18].…”

Section: Introductionmentioning

confidence: 99%

Neuroplastin in Neuropsychiatric Diseases

Lin

Liang

Herrera-Molina

et al. 2021

Genes

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Molecular mechanisms underlying neuropsychiatric and neurodegenerative diseases are insufficiently elucidated. A detailed understanding of these mechanisms may help to further improve medical intervention. Recently, intellectual abilities, creativity, and amnesia have been associated with neuroplastin, a cell recognition glycoprotein of the immunoglobulin superfamily that participates in synapse formation and function and calcium signaling. Data from animal models suggest a role for neuroplastin in pathways affected in neuropsychiatric and neurodegenerative diseases. Neuroplastin loss or disruption of molecular pathways related to neuronal processes has been linked to various neurological diseases, including dementia, schizophrenia, and Alzheimer’s disease. Here, we review the molecular features of the cell recognition molecule neuroplastin, and its binding partners, which are related to neurological processes and involved in learning and memory. The emerging functions of neuroplastin may have implications for the treatment of diseases, particularly those of the nervous system.

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Neuregulin-1 alpha, the underestimated molecule: emerging new roles in normal brain function and the pathophysiology of schizophrenia?

Abstract: We comment here, from a schizophrenia research perspective, on a recent paper of Ghahramani Seno et al., which clearly shows that the splice variant neuregulin-1 alpha is able to regulate multiple genes involved in phosphorylation, acetylation, and generation of splice variants.

Cited by 4 publications

References 16 publications

Inhibition of the Schizophrenia-Associated MicroRNA miR-137 Disrupts Nrg1α Neurodevelopmental Signal Transduction

Inhibition of the Schizophrenia-Associated MicroRNA miR-137 Disrupts Nrg1α Neurodevelopmental Signal Transduction

Human cell adhesion molecules: annotated functional subtypes and overrepresentation of addiction‐associated genes

Neuroplastin in Neuropsychiatric Diseases

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