Regenerating Islet-derived 1α (Reg-1α) Protein Is New Neuronal Secreted Factor That Stimulates Neurite Outgrowth via Exostosin Tumor-like 3 (EXTL3) Receptor

Ba, Isabelle Acquatella-Tran Van; Marchal, Stéphane; François, Florence; Silhol, Michelle; Lleres, Coline; Michel, Bernard; Benyamin, Yves; Verdier, Jean‐Michel; Trousse, Françoise; Marcilhac, Anne

doi:10.1074/jbc.m111.260349

Cited by 38 publications

(29 citation statements)

References 27 publications

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“…A Manhattan plot for the two tailed tests is shown in Figure 1, and the top 20 results are displayed in Table 2. The most significant result emerged for a variant on chromosome 2 (rs879022, bp 79364463, p = 4.72e-09) located in a cluster of genes that encode for a family of proteins primarily excreted by the pancreas that are associated with islet regeneration (REG proteins encoded by REG1A, REG1B, REG3A, REG3G ), but are also expressed in the CNS and related to neurodevelopment in the fetal brain (de la Monte et al ., 1990) and neuronal sprouting and synaptogenesis in the adult brain (Acquatella-Tran Van Ba et al ., 2012). The associated variant was located in the pseudogene, REG1P, that was likely produced by a duplication event related to one of the primary genes in the cluster (Figure 2).…”

Section: Resultsmentioning

confidence: 99%

Single nucleotide polymorphisms in the REG‐CTNNA2 region of chromosome 2 and NEIL3 associated with impulsivity in a Native American sample

Ehlers

Gizer

Bizon

et al. 2016

Genes Brain and Behavior

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Impulsivity is a multi-faceted construct that, while characterized by a set of correlated dimensions, is centered around a core definition that involves acting suddenly in an unplanned manner without consideration for the consequences of such behavior. Several psychiatric disorders include impulsivity as a criterion, and thus it has been suggested that it may link a number of different behavioral disorders, including substance abuse. Native Americans experience some of the highest rates of substance abuse of all US ethnic groups. The described analyses used data from a low coverage whole genome sequence scan to conduct a genome-wide association study of an impulsivity phenotype in an American Indian community sample (n=658). Demographic and clinical information were obtained using a semi-structured interview. Impulsivity was assessed using a scale derived from the Maudsley personality inventory that combines both novelty-seeking and lack of planning items. The impulsivity score was tested for association with each variant adjusted for demographic variables, and corrected for ancestry and kinship, using EMMAX. Simulations were conducted to calculate empirical p-values. Genome-wide significant findings were observed for a variant 50 kb upstream from catenin cadherin-associated protein, alpha 2 (CTNNA2), a neuronal specific catenin, in the REG gene cluster. A meta-analysis of genome-wide association studies had previously identified common variants in CTNNA2 as being associated with excitement seeking. A second locus upstream of NEIL3 on chromosome 4 also achieved genome-wide significance. The association between sequence variants in these regions suggests their potential roles in the genetic regulation of this phenotype in this population.

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Section: Resultsmentioning

confidence: 99%

Single nucleotide polymorphisms in the REG‐CTNNA2 region of chromosome 2 and NEIL3 associated with impulsivity in a Native American sample

Ehlers

Gizer

Bizon

et al. 2016

Genes Brain and Behavior

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“…Its transient overexpression stimulates neurite outgrowth. The deposits of Reg-1α was found in the brain of very early stage Alzheimer disease patients and may reflect aberrant neuritic sprouting associated with synaptic disconnection and dementia (Acquatella-Tran Van Ba et al, 2012). Its putative receptor is ‘exostosin tumor-like 3′ protein encoded by the EXTL3 gene (decreased 2.396 fold at P7; Figure 3).…”

Section: Discussionmentioning

confidence: 99%

Altered gene expression in early postnatal monoamine oxidase A knockout mice

et al. 2017

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We reported previously that monoamine oxidase (MAO) A knockout (KO) mice show increased serotonin (5-hydroxytryptamine, 5-HT) levels and autistic-like behaviors characterized by repetitive behaviors, and anti-social behaviors. We showed that administration of the serotonin synthesis inhibitor para-chlorophenylalanine (pCPA) from post-natal day 1 (P1) through 7 (P7) in MAO A KO mice reduced the serotonin level to normal and reverses the repetitive behavior. These results suggested that the altered gene expression at P1 and P7 may be important for the autistic-like behaviors seen in MAO A KO mice and was studied here. In this study, Affymetrix mRNA array data for P1 and P7 MAO A KO mice were analyzed using Partek Genomics Suite and Ingenuity Pathways Analysis to identify genes differentially expressed versus wild-type and assess their functions and relationships. The number of significant differentially expressed genes (DEGs) varied with age: P1 (664) and P7 (3307) [false discovery rate (FDR) <0.05, fold-change (FC) >1.5 for autism-linked genes and >2.0 for functionally categorized genes]. Eight autism-linked genes were differentially expressed in P1 (upregulated: NLGN3, SLC6A2; down-regulated: HTR2C, MET, ADSL, MECP2, ALDH5A1, GRIN3B) while four autism-linked genes were differentially expressed at P7 (upregulated: HTR2B; downregulated: GRIN2D, GRIN2B, CHRNA4). Many other genes involved in neurodevelopment, apoptosis, neurotransmission, and cognitive function were differentially expressed at P7 in MAO A KO mice. This result suggests that modulation of these genes by the increased serotonin may lead to neurodevelopmental alteration in MAO A KO mice and results in autistic-like behaviors.

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“…A homology search revealed that the cDNA was a homologue of a human multiple exostoses (EXT)-like gene, especially the human EXT-like gene 3 (EXTL3; over 97 % amino acid identity), indicating that the receptor was encoded by the EXTL3 gene and that it mediated growth signals of the Reg protein for β cell regeneration. After the report that the Extl3 gene encodes the Reg receptor [45], Acquatella-Tran Van Ba et al confirmed that Extl3 is a Reg receptor [46], and several groups also reported Extl3 as a Reg protein receptor [47][48][49][50][51]. In a later study, further advances in the Reg receptor (Extl3) were reported; Reg receptor (Extl3) overexpression in pancreatic β cells as well as Reg protein addition to β cells induced the activating transcription factor-2 (ATF-2) activation [52], and a β cell-specific knockout for Extl3 resulted in abnormal islet morphology with reduced β cell proliferation [53].…”

Section: Reg Receptormentioning

confidence: 90%

“…The Reg receptor (EXTL3) mRNA expression was also detected in the liver, heart, kidney, spleen, thymus, stomach, small intestine, and colon, as well as pancreatic acinar and ductal cells, suggesting that the Reg-Reg receptor system is involved with a variety of cell types in addition to β cells [29,30,[45][46][47][48][49].…”

Section: Reg Receptormentioning

confidence: 92%

Significance of Interleukin-6/STAT Pathway for the Gene Expression of REG Iα, a New Autoantigen in Sjögren’s Syndrome Patients, in Salivary Duct Epithelial Cells

Fujimura

Fujimoto

Itaya‐Hironaka

et al. 2016

Clinic Rev Allerg Immunol

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The regenerating gene, Reg, was originally isolated from a rat regenerating islet complementary DNA (cDNA) library, and its human homologue was named REG Iα. Recently, we reported that REG Iα messenger RNA (mRNA), as well as its product, was overexpressed in ductal epithelial cells in the salivary glands of Sjögren's syndrome patients. Furthermore, autoantibodies against REG Iα were found in the sera of Sjögren's syndrome patients, and the patients who were positive for the anti-REG Iα antibody showed significantly lower saliva secretion than antibody-negative patients. We found the mechanism of REG Iα induction in salivary ductal epithelial cells. Reporter plasmid containing REG Iα promoter (-1190/+26) upstream of a luciferase gene was introduced into human NS-SV-DC and rat A5 salivary ductal cells. The cells were treated with several cytokines (interleukin (IL)-6, IL-8, etc.), upregulated in Sjögren's syndrome salivary ducts, and the transcriptional activity was measured. IL-6 stimulation significantly enhanced the REG Iα promoter activity in both cells. Deletion analysis revealed that the -141∼-117 region of the REG Iα gene was responsible for the promoter activation by IL-6, which contains a consensus sequence for signal transducer and activator of transcription (STAT) binding. The introduction of small interfering RNA for human STAT3 abolished IL-6-induced REG Iα transcription. These results indicated that IL-6 stimulation induced REG Iα transcription through STAT3 activation and binding to the REG Iα promoter in salivary ductal cells. This dependence of REG Iα induction upon IL-6/STAT in salivary duct epithelial cells may play an important role in the pathogenesis/progression of Sjögren's syndrome.

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Regenerating Islet-derived 1α (Reg-1α) Protein Is New Neuronal Secreted Factor That Stimulates Neurite Outgrowth via Exostosin Tumor-like 3 (EXTL3) Receptor

Cited by 38 publications

References 27 publications

Single nucleotide polymorphisms in the REG‐CTNNA2 region of chromosome 2 and NEIL3 associated with impulsivity in a Native American sample

Single nucleotide polymorphisms in the REG‐CTNNA2 region of chromosome 2 and NEIL3 associated with impulsivity in a Native American sample

Altered gene expression in early postnatal monoamine oxidase A knockout mice

Significance of Interleukin-6/STAT Pathway for the Gene Expression of REG Iα, a New Autoantigen in Sjögren’s Syndrome Patients, in Salivary Duct Epithelial Cells

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