Publications by authors named "Yoshihiro Morikawa"

45 Publications

Essential roles of oncostatin M receptor β signaling in renal crystal formation in mice.

Sci Rep 2020 10 13;10(1):17150. Epub 2020 Oct 13.

Department of Anatomy and Neurobiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan.

Oncostatin M (OSM), a member of the IL-6 family of cytokines, has important roles in renal diseases. The relationship between OSM and kidney stone disease, however, remains unclear. To investigate the roles of OSM in the development of kidney stone disease, we generated a mouse model of renal crystal formation using OSM receptor β (OSMRβ)-deficient mice (OSMRβ mice). There were fewer renal crystal deposits in OSMRβ mice than in wild-type (WT) mice. Crystal-binding molecules (osteopontin, annexin A1, and annexin A2), inflammatory cytokines (TNF-α and IL-1β), and fibrosis markers (TGF-β, collagen 1a2, and α-smooth muscle actin) were also decreased in the kidneys of OSMRβ mice compared with those in WT mice. Immunofluorescence staining showed that OSMRβ was expressed in renal tubular epithelial cells (RTECs) and renal fibroblasts in the model of renal crystal formation. In the cultured RTECs and renal fibroblasts, OSM directly induced the expression of crystal-binding molecules and fibrosis markers. Expressions of inflammatory cytokines were increased by stimulation with OSM in cultured renal fibroblasts. OSM may promote the formation of renal crystal deposits by directly acting on RTECs and renal fibroblasts to produce crystal-binding molecules and inflammatory cytokines.
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http://dx.doi.org/10.1038/s41598-020-74198-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553912PMC
October 2020

Abnormal behaviours relevant to neurodevelopmental disorders in Kirrel3-knockout mice.

Sci Rep 2018 01 23;8(1):1408. Epub 2018 Jan 23.

Department of Anatomy and Neurobiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan.

In the nervous system, Kirrel3 is involved in neuronal migration, axonal fasciculation, and synapse formation. Recently, genetic links have been reported between mutations in the KIRREL3 gene and increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability. To elucidate the causal relationship between KIRREL3 deficiency and behavioural abnormalities relevant to neurodevelopmental disorders, we generated global Kirrel3-knockout (Kirrel3) mice and investigated the detailed behavioural phenotypes. In the three-chambered social approach test, Kirrel3 mice displayed a significant preference for a mouse over a non-social object but no significant preference for a stranger mouse over a familiar mouse. Ultrasonic communications, including pup-to-mother calls, male-female courtship vocalisation and resident responses to intruder, were significantly impaired in Kirrel3 mice. Significant increases in locomotor activity and repetitive rearing were also observed in Kirrel3 mice. Furthermore, the performance of Kirrel3 mice in the rotarod test was significantly better than that of wild-type mice. In the acoustic startle test, Kirrel3 mice were significantly hypersensitive to acoustic stimuli. Anxiety-related behaviours and spatial or fear memory acquisition were normal in Kirrel3 mice. These findings suggest that Kirrel3 mice exhibit autistic-like behaviours, including social and communicative deficits, repetitive behaviours, and sensory abnormalities, as well as hyperactivity.
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http://dx.doi.org/10.1038/s41598-018-19844-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780462PMC
January 2018

Oncostatin M in the development of metabolic syndrome and its potential as a novel therapeutic target.

Anat Sci Int 2018 Mar 4;93(2):169-176. Epub 2017 Nov 4.

Department of Anatomy and Neurobiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan.

Oncostatin M (OSM), a member of the IL-6 family of cytokines, plays an important role in various biologic actions, including cell growth, neuronal development, and inflammatory responses. Recently, we demonstrated the unique relationship between OSM and metabolic syndrome in mice. Mice lacking OSM receptor β subunit (OSMRβ mice) exhibited late-onset obesity. Before the onset of obesity, adipose tissue inflammation and insulin resistance were observed in OSMRβ mice. In addition, high-fat diet-induced metabolic disorders, including obesity, adipose tissue inflammation, insulin resistance, and hepatic steatosis, were aggravated in OSMRβ mice compared to those in wild-type mice. Consistent with these findings, OSM treatment dramatically improved these metabolic disorders in the mouse model of metabolic syndrome. Interestingly, OSM directly changed the phenotypes of adipose tissue macrophages toward anti-inflammatory M2 type. Furthermore, fatty acid content in the hepatocytes was decreased by OSM through expression regulation of several key enzymes of hepatic lipid metabolism. These findings suggest that OSM is a novel therapeutic target for metabolic syndrome.
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http://dx.doi.org/10.1007/s12565-017-0421-yDOI Listing
March 2018

Oncostatin M is a potential agent for the treatment of obesity and related metabolic disorders: a study in mice.

Diabetologia 2015 Aug 14;58(8):1868-76. Epub 2015 May 14.

Department of Anatomy and Neurobiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan.

Aims/hypothesis: Obesity and insulin resistance are closely associated with adipose tissue dysfunction caused by the abnormal recruitment of inflammatory cells, including macrophages. Oncostatin M (OSM), a member of the IL-6 family of cytokines, plays important roles in a variety of biological functions including the regulation of inflammatory responses. In previous reports, we have demonstrated that mice deficient in the OSM receptor β subunit show obesity, adipose tissue inflammation, insulin resistance and hepatic steatosis, all of which are exacerbated by feeding the mice a high-fat diet. These results prompted us to test the therapeutic effects of OSM on obesity-induced metabolic disorders using mouse models of obesity.

Methods: In diet-induced obese and ob/ob mice, metabolic variables were assessed physiologically, histologically and biochemically after the intraperitoneal injection of recombinant mouse OSM twice a day for 1 week.

Results: Treatment with OSM improved obesity, adipose tissue inflammation, insulin resistance and hepatic steatosis in both mouse models. Although OSM reduced food intake, such therapeutic effects of OSM were observed even under pair-feeding conditions. Functionally, OSM directly changed the phenotype of adipose tissue macrophages from M1 type (inflammatory) to M2 type (anti-inflammatory). In the liver, OSM suppressed the expression of genes related to fatty acid synthesis and increased the expression of genes related to fatty acid oxidation. Furthermore, OSM decreased lipid absorption and increased the expression of active glucagon-like peptide-1 in the intestine.

Conclusions/interpretation: We showed that OSM is a novel candidate to act as a powerful therapeutic agent for the treatment of obesity-induced metabolic disorders.
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http://dx.doi.org/10.1007/s00125-015-3613-9DOI Listing
August 2015

Deficiency of oncostatin M receptor β (OSMRβ) exacerbates high-fat diet-induced obesity and related metabolic disorders in mice.

J Biol Chem 2014 May 2;289(20):13821-37. Epub 2014 Apr 2.

From the Department of Anatomy and Neurobiology, Wakayama Medical University, Wakayama 641-8509, Japan and

Oncostatin M (OSM) belongs to the IL-6 family of cytokines and has diverse biological effects, including the modulation of inflammatory responses. In the present study we analyzed the roles of OSM signaling in obesity and related metabolic disorders. Under a high-fat diet condition, OSM receptor β subunit-deficient (OSMRβ(-/-)) mice exhibited increases in body weight and food intake compared with those observed in WT mice. In addition, adipose tissue inflammation, insulin resistance, and hepatic steatosis were more severe in OSMRβ(-/-) mice than in wild-type (WT) mice. These metabolic phenotypes did not improve when OSMRβ(-/-) mice were pair-fed with WT mice, suggesting that the effects of OSM signaling on these phenotypes are independent of the increases in the body weight and food intake. In the liver of OSMRβ(-/-) mice, the insulin-induced phosphorylation of p70 S6 kinase remained intact, whereas insulin-induced FOXO1 phosphorylation was impaired. In addition, OSMRβ(-/-) mice displayed a higher expression of genes related to de novo lipogenesis in the liver than WT mice. Furthermore, treatment of genetically obese ob/ob mice with OSM improved insulin resistance, adipose tissue inflammation, and hepatic steatosis. Intraportal administration of OSM into ob/ob mice activated STAT3 and increased the expression of long-chain acyl-CoA synthetase (ACSL) 3 and ACSL5 with decreased expression of fatty acid synthase in the liver, suggesting that OSM directly induces lipolysis and suppresses lipogenesis in the liver of obese mice. These findings suggest that defects in OSM signaling promote the deterioration of high-fat diet-induced obesity and related metabolic disorders.
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http://dx.doi.org/10.1074/jbc.M113.542399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022856PMC
May 2014

Lack of oncostatin M receptor β leads to adipose tissue inflammation and insulin resistance by switching macrophage phenotype.

J Biol Chem 2013 Jul 11;288(30):21861-75. Epub 2013 Jun 11.

Department of Anatomy and Neurobiology, Wakayama Medical University, Wakayama 641-8509, Japan.

Oncostatin M (OSM), a member of the IL-6 family of cytokines, plays important roles in a variety of biological functions, including inflammatory responses. However, the roles of OSM in metabolic diseases are unknown. We herein analyzed the metabolic parameters of OSM receptor β subunit-deficient (OSMRβ(-/-)) mice under normal diet conditions. At 32 weeks of age, OSMRβ(-/-) mice exhibited mature-onset obesity, severer hepatic steatosis, and insulin resistance. Surprisingly, insulin resistance without obesity was observed in OSMRβ(-/-) mice at 16 weeks of age, suggesting that insulin resistance precedes obesity in OSMRβ(-/-) mice. Both OSM and OSMRβ were expressed strongly in the adipose tissue and little in some other metabolic organs, including the liver and skeletal muscle. In addition, OSMRβ is mainly expressed in the adipose tissue macrophages (ATMs) but not in adipocytes. In OSMRβ(-/-) mice, the ATMs were polarized to M1 phenotypes with the augmentation of adipose tissue inflammation. Treatment of OSMRβ(-/-) mice with an anti-inflammatory agent, sodium salicylate, improved insulin resistance. In addition, the stimulation of a macrophage cell line, RAW264.7, and peritoneal exudate macrophages with OSM resulted in the increased expression of M2 markers, IL-10, arginase-1, and CD206. Furthermore, treatment of C57BL/6J mice with OSM increased insulin sensitivity and polarized the phenotypes of ATMs to M2. Thus, OSM suppresses the development of insulin resistance at least in part through the polarization of the macrophage phenotypes to M2, and OSMRβ(-/-) mice provide a unique mouse model of metabolic diseases.
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http://dx.doi.org/10.1074/jbc.M113.461905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724642PMC
July 2013

Dynamic expression pattern of leucine-rich repeat neuronal protein 4 in the mouse dorsal root ganglia during development.

Neurosci Lett 2013 Aug 20;548:73-8. Epub 2013 May 20.

Department of Anatomy and Neurobiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama 641-8509, Japan.

A member of leucine-rich repeat neuronal protein (Lrrn) family, Lrrn4, is a type I transmembrane protein and functions as a cell adhesion molecule. In our previous report, Lrrn4 is expressed in a subset of small-sized dorsal root ganglion (DRG) neurons of the adult mice. In the present study, we investigated the expression pattern of Lrrn4 in the developing DRGs. The expression of Lrrn4 was first observed in 7% of total DRG neurons at embryonic day (E) 13.5, gradually increasing to 44% at E17.5, reached the maximum level between E17.5 and postnatal day (P) 7, decreased drastically after P7, and became the adult level by P14. Interestingly, the expression of Lrrn4 was mainly observed in TrkC-positive neurons at E13.5, and the predominant expression was shifted from TrkC-positive neurons to TrkA-positive neurons between E15.5 and E17.5. As the central afferents of TrkC-positive and TrkA-positive neurons begin to penetrate into the spinal cord to form synapse with secondary neurons at E13.5 and E15.5, respectively, the time course of Lrrn4 expression may suggest the contribution of Lrrn4 to synaptic formation. In addition, some cell adhesion molecules containing leucine-rich repeat are identified as synaptic adhesion molecules, suggesting that the spatiotemporal expression pattern of Lrrn4 contributes to the development of synaptic function in the DRG neurons.
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http://dx.doi.org/10.1016/j.neulet.2013.05.024DOI Listing
August 2013

Expression pattern of leucine-rich repeat neuronal protein 4 in adult mouse dorsal root ganglia.

Neurosci Lett 2012 Nov 13;531(1):24-9. Epub 2012 Oct 13.

Department of Anatomy and Neurobiology, Wakayama Medical University, 811-1, Kimiidera, Wakayama City, Wakayama 641-8509, Japan.

A member of leucine-rich repeat neuronal protein family, leucine-rich repeat neuronal protein 4 (Lrrn4), is a type I transmembrane protein. Previously, we have reported that Lrrn4 is expressed in various regions of the central nervous system (CNS) and involved in the memory retention. However, little is known about the role of Lrrn4 in the peripheral nervous system (PNS). Northern blot analysis revealed that Lrrn4 mRNA was expressed predominantly in the dorsal root ganglia (DRGs) with low levels in some regions of the CNS. To identify Lrrn4-expressing cells in the DRGs, we performed in situ hybridization histochemistry and LacZ staining in Lrrn4-heterozygous (Lrrn4+/-) mice generated by the replacement of Lrrn4 gene with β-galactosidase gene. In the adult DRGs, 8% of total DRG neurons contained Lrrn4 mRNA, which was exclusively expressed in the small-sized neurons. LacZ staining combined with immunohistochemistry revealed that approximately 42% and 58% of Lrrn4-positive neurons contained receptor tyrosine kinase A (TrkA)- and Ret-immunoreactivity, respectively. After sciatic nerve axotomy, the expression of Lrrn4 mRNA was reduced in injured side of the DRGs. Thus, Lrrn4 is expressed in a subset of nociceptive neurons and might contribute to the maintenance of nociceptive circuits.
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http://dx.doi.org/10.1016/j.neulet.2012.10.009DOI Listing
November 2012

Regulation of AMP-activated protein kinase signaling by AFF4 protein, member of AF4 (ALL1-fused gene from chromosome 4) family of transcription factors, in hypothalamic neurons.

J Biol Chem 2012 Jun 23;287(24):19985-96. Epub 2012 Apr 23.

Department of Anatomy and Neurobiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.

In the hypothalamus, fasting induces a member of the AF4 family of transcription factors, AFF4, which was originally identified as a fusion partner of the mixed-lineage leukemia gene in infant acute lymphoblastic leukemia. However, the roles of AFF4 in the hypothalamus remain unclear. We show herein that expression of AFF4 increased upon addition of ghrelin and fasting in the growth hormone secretagogue receptor-expressing neurons of the hypothalamus. In the growth hormone secretagogue receptor-expressing hypothalamic neuronal cell line GT1-7, ghrelin markedly induced expression of AFF4 in a time- and dose-dependent manner. Overexpression of AFF4 in GT1-7 cells specifically induced expression of the AMP-activated protein kinase (AMPK) α2 subunit but failed to induce other AMPK subunits and AMPK upstream kinases. The promoter activity of the AMPKα2 gene increased upon addition of AFF4, suggesting that AFF4 regulates transcription of the AMPKα2 gene. Additionally, AFF4 also increased the phosphorylation of acetyl-CoA carboxylase α (ACCα), a downstream target of AMPK. In GT1-7 cells, ghrelin phosphorylated ACCα through AMPKα phosphorylation in the early phase (15 min) of the activation. However, ghrelin-induced expression of AMPKα2 and phosphorylation of ACCα in the late phase (2 h) of the activation were independent of AMPKα phosphorylation. Attenuation of expression of AFF4 by its siRNA in GT1-7 cells decreased ghrelin-induced AMPKα2 expression and ACCα phosphorylation in the late phase of the activation. AFF4 may therefore help to maintain activation of AMPK downstream signaling under conditions of prolonged stimulation with ghrelin, such as during fasting.
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http://dx.doi.org/10.1074/jbc.M112.367854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370182PMC
June 2012

Site-specific subtypes of macrophages recruited after peripheral nerve injury.

Neuroreport 2011 Dec;22(17):911-7

Department of Anatomy and Neurobiology, Wakayama Medical University, Wakayama, Japan.

After partial ligation of mouse sciatic nerve, the subtypes of macrophages were examined in the injured nerve and dorsal root ganglia (DRGs). Many M1 macrophages, which were inducible nitric oxide synthase (iNOS)-positive and arginase-1 (Arg-1)-negative, and neutrophils infiltrated the injured nerve. In contrast, almost all macrophages infiltrating the ipsilateral side of DRGs after the nerve injury were iNOS⁻/Arg-1⁺, M2 type. The infiltration of M1 and M2 macrophages was first observed in the injured nerve and ipsilateral DRGs on days 1 and 2, respectively. In addition, the macrophage infiltration preceded the activation of microglia in the ipsilateral dorsal horn of spinal cord. Thus, infiltrating macrophages after peripheral nerve injury may play unique roles dependent on the location in the development of neuropathic pain.
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http://dx.doi.org/10.1097/WNR.0b013e32834cd76aDOI Listing
December 2011

Oncostatin M regulates neural precursor activity in the adult brain.

Dev Neurobiol 2011 Jul;71(7):619-33

The Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia.

The regulation of neural precursor cell (NPC) activity is the major determinant of the rate of neuronal production in neurogenic regions of the adult brain. Here, we show that Oncostatin M (Osm) and its receptor, OsmRβ, are both expressed in the subventricular zone (SVZ) and that in contradistinction to leukemia inhibitory factor and ciliary neutrophic factor, Osm directly inhibits the proliferation of adult NPCs as measured by a decreased level of neurosphere formation in vitro. Similarly, intraventricular infusion of Osm dramatically decreases the pool of NPCs in both the SVZ and the hippocampus. In keeping with the inhibitory action of Osm, we reveal that mice lacking OsmRβ have substantially more NPCs in the SVZ, the hippocampus and the olfactory bulb, demonstrating that endogenous Osm signaling is important for NPC homeostasis. Finally, we show that Osm can also inhibit clonal growth of glioblastoma-derived neurospheres, further supporting the close link between NPCs and tumor stem cells.
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http://dx.doi.org/10.1002/dneu.20871DOI Listing
July 2011

Regulation of ghrelin signaling by a leptin-induced gene, negative regulatory element-binding protein, in the hypothalamic neurons.

J Biol Chem 2010 Nov 28;285(48):37884-94. Epub 2010 Sep 28.

Department of Anatomy and Neurobiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.

Leptin, the product of the ob gene, plays important roles in the regulation of food intake and body weight through its receptor in the hypothalamus. To identify novel transcripts induced by leptin, we performed cDNA subtraction based on selective suppression of the polymerase chain reaction by using mRNA prepared from the forebrain of leptin-injected ob/ob mice. One of the genes isolated was a mouse homolog of human negative regulatory element-binding protein (NREBP). Its expression was markedly increased by leptin in the growth hormone secretagogue-receptor (GHS-R)-positive neurons of the arcuate nucleus and ventromedial hypothalamic nucleus. The promoter region of GHS-R contains one NREBP binding sequence, suggesting that NREBP regulates GHS-R transcription. Luciferase reporter assays showed that NREBP repressed GHS-R promoter activity in a hypothalamic neuronal cell line, GT1-7, and its repressive activity was abolished by the replacement of negative regulatory element in GHS-R promoter. Overexpression of NREBP reduced the protein expression of endogenous GHS-R without affecting the expression of ob-Rb in GT1-7 cells. To determine the functional importance of NREBP in the hypothalamus, we assessed the effects of NREBP on ghrelin action. Although phosphorylation of AMP-activated protein kinase α (AMPKα) was induced by ghrelin in GT1-7 cells, NREBP repressed ghrelin-induced AMPKα phosphorylation. These results suggest that leptin-induced NREBP is an important regulator of GHS-R expression in the hypothalamus and provides a novel molecular link between leptin and ghrelin signaling.
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http://dx.doi.org/10.1074/jbc.M110.148973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988391PMC
November 2010

TIMP-3 recruits quiescent hematopoietic stem cells into active cell cycle and expands multipotent progenitor pool.

Blood 2010 Nov 26;116(22):4474-82. Epub 2010 Aug 26.

Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

Regulating transition of hematopoietic stem cells (HSCs) between quiescent and cycling states is critical for maintaining homeostasis of blood cell production. The cycling states of HSCs are regulated by the extracellular factors such as cytokines and extracellular matrix; however, the molecular circuitry for such regulation remains elusive. Here we show that tissue inhibitor of metalloproteinase-3 (TIMP-3), an endogenous regulator of metalloproteinases, stimulates HSC proliferation by recruiting quiescent HSCs into the cell cycle. Myelosuppression induced TIMP-3 in the bone marrow before hematopoietic recovery. Interestingly, TIMP-3 enhanced proliferation of HSCs and promoted expansion of multipotent progenitors, which was achieved by stimulating cell-cycle entry of quiescent HSCs without compensating their long-term repopulating activity. Surprisingly, this effect did not require metalloproteinase inhibitory activity of TIMP-3 and was possibly mediated through a direct inhibition of angiopoietin-1 signaling, a critical mediator for HSC quiescence. Furthermore, bone marrow recovery from myelosuppression was accelerated by over-expression of TIMP-3, and in turn, impaired in TIMP-3-deficient animals. These results suggest that TIMP-3 may act as a molecular cue in response to myelosuppression for recruiting dormant HSCs into active cell cycle and may be clinically useful for facilitating hematopoietic recovery after chemotherapy or ex vivo expansion of HSCs.
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http://dx.doi.org/10.1182/blood-2010-01-266528DOI Listing
November 2010

TIM1 is an endogenous ligand for LMIR5/CD300b: LMIR5 deficiency ameliorates mouse kidney ischemia/reperfusion injury.

J Exp Med 2010 Jul 21;207(7):1501-11. Epub 2010 Jun 21.

Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.

Leukocyte mono-immunoglobulin (Ig)-like receptor 5 (LMIR5)/CD300b is a DAP12-coupled activating receptor predominantly expressed in myeloid cells. The ligands for LMIR have not been reported. We have identified T cell Ig mucin 1 (TIM1) as a possible ligand for LMIR5 by retrovirus-mediated expression cloning. TIM1 interacted only with LMIR5 among the LMIR family, whereas LMIR5 interacted with TIM4 as well as TIM1. The Ig-like domain of LMIR5 bound to TIM1 in the vicinity of the phosphatidylserine (PS)-binding site within the Ig-like domain of TIM1. Unlike its binding to TIM1 or TIM4, LMIR5 failed to bind to PS. LMIR5 binding did not affect TIM1- or TIM4-mediated phagocytosis of apoptotic cells, and stimulation with TIM1 or TIM4 induced LMIR5-mediated activation of mast cells. Notably, LMIR5 deficiency suppressed TIM1-Fc-induced recruitment of neutrophils in the dorsal air pouch, and LMIR5 deficiency attenuated neutrophil accumulation in a model of ischemia/reperfusion injury in the kidneys in which TIM1 expression is up-regulated. In that model, LMIR5 deficiency resulted in ameliorated tubular necrosis and cast formation in the acute phase. Collectively, our results indicate that TIM1 is an endogenous ligand for LMIR5 and that the TIM1-LMIR5 interaction plays a physiological role in immune regulation by myeloid cells.
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http://dx.doi.org/10.1084/jem.20090581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901072PMC
July 2010

The absence of interleukin-6 enhanced arsenite-induced renal injury by promoting autophagy of tubular epithelial cells with aberrant extracellular signal-regulated kinase activation.

Am J Pathol 2010 Jan 11;176(1):40-50. Epub 2009 Dec 11.

Department of Forensic Medicine, Wakayama Medical University, Wakayama 641-8509, Japan.

Sodium arsenite (NaAs)-induced autophagic cell death (ACD) of a mouse renal tubular epithelial cell line (mProx24), which expresses enhanced levels of interleukin-6 (IL-6), was reduced by the suppression of autophagy by 3-methyladenine or Atg7 knockdown. The inhibition of the IL-6/signal transducer and activator of transcription 3 (STAT3) signal pathway by anti-IL-6 antibody or a Jak2 inhibitor (AG490) exaggerated ACD of mProx24 cells after NaAs challenge, attenuating STAT3 activation and reciprocally enhancing extracellular signal-regulated kinase (ERK) phosphorylation. In contrast, an ERK inhibitor, PD98059, reduced NaAs-induced ACD in mProx24 cells. Subcutaneous injection of NaAs (12.5 mg/kg) into BALB/c (wild-type) mice enhanced intrarenal expression of IL-6, mainly produced by tubular cells, and caused severe renal injury characterized by hemorrhages, acute tubular necrosis, cast formation, and brush border disappearance, with increases in serum urea nitrogen (blood urea nitrogen) and creatinine levels. In addition, IL-6-deficient (IL-6(-/-)) mice exhibited exaggerated histopathological changes with higher blood urea nitrogen and creatinine levels. Moreover, in IL-6(-/-) mice treated with NaAs, ACD in renal tubular cells was significantly augmented, along with diminished STAT3 activation and reciprocal enhancement of ERK signaling, compared with wild-type mice. Finally, the administration of exogenous IL-6 into wild-type mice significantly reduced NaAs-induced ACD along with diminished ERK activation and eventually alleviated acute renal dysfunction. Thus, IL-6/STAT3 signal pathway could inhibit ERK activation, a crucial step for ACD, eventually attenuating NaAs-induced renal dysfunction.
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http://dx.doi.org/10.2353/ajpath.2010.090146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797868PMC
January 2010

Detailed expression pattern of Foxp1 and its possible roles in neurons of the spinal cord during embryogenesis.

Dev Neurosci 2009 30;31(6):511-22. Epub 2009 Sep 30.

Department of Anatomy and Neurobiology, Wakayama Medical University, Wakayama, Japan.

A member of winged-helix/forkhead transcription factors, Foxp1, is expressed in the developing spinal cord during mouse embryogenesis. To shed light on the potential role of Foxp1 in neurons of the developing spinal cord, we investigated the detailed expression pattern of Foxp1 between embryonic day (E) 9.5 and E17.5. At E10.25, some postmitotic neurons with strong expression of Foxp1 (Foxp1(high)) were first detected in the ventral half of the brachial spinal cord. By E11.5, Foxp1(high) neurons increased in the ventral spinal cord at the limb levels. All of Foxp1(high) neurons at the limb levels were Islet2(+)/Lhx3(-) motor neurons (MNs) of the lateral motor column and some neurons that expressed Foxp1 weakly (Foxp1(low)) at the thoracic level were MNs of the preganglionic motor column. Between E12.5 and E17.5, Foxp1(low) neurons were also observed in the intermediate zone throughout the ventral spinal cord, all of which were Pax2(+), En1(+), Evx1(-), Chx10(-), Gata3(-), and Lhx3(-) V1 interneurons. Interestingly, no colocalization of Foxp1 with Lhx3 was observed in the developing spinal cord. In addition, overexpression of Foxp1 markedly attenuated the endogenous expression of Lhx3 in a neuroendocrine cell line. Chromatin immunoprecipitation assays in a neuronal cell line and E13.5 spinal cords revealed an interaction between Foxp1 and the consensus motif in the Lhx3 promoter. These results suggest that Foxp1 may play some important roles in the determination of neuronal fates of the ventral spinal cord, possibly through the suppression of Lhx3 expression.
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http://dx.doi.org/10.1159/000243715DOI Listing
January 2010

Wnt modulators, SFRP-1, and SFRP-2 are expressed in osteoblasts and differentially regulate hematopoietic stem cells.

Biochem Biophys Res Commun 2009 Dec 22;390(1):65-70. Epub 2009 Sep 22.

Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.

Wnt signaling has been implicated in the self-renewal of hematopoietic stem cells (HSCs). Secreted frizzled-related proteins (SFRPs) are a family of soluble proteins containing a region homologous to a receptor for Wnt, Frizzled, and are thought to act as endogenous modulators for Wnt signaling. This study examined the role of SFRPs in HSC regulation. Among the four family members, SFRP-1 and SFRP-2 are specifically induced in the bone marrow in response to myelosuppression, and immunostaining revealed that both proteins were expressed in osteoblasts. Interestingly, SFRP-1 reduced the number of multipotent progenitors in in vitro culture of CD34(-)KSL cells, while SFRP-2 did not. Furthermore, SFRP-1 compromised the long-term repopulating activity of HSCs, whereas SFRP-2 did not affect or even enhanced it in the same setting. These results indicate that although both SFRP-1 and SFRP-2 act as inhibitors for Wnt signaling in vitro, they differentially affect the homeostasis of HSCs.
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http://dx.doi.org/10.1016/j.bbrc.2009.09.067DOI Listing
December 2009

Oncostatin M deficiency leads to thymic hypoplasia, accumulation of apoptotic thymocytes and glomerulonephritis.

Eur J Immunol 2009 Jun;39(6):1664-70

Institute of Molecular and Cellular Biosciences, University of Tokyo Bunkyo-ku, Tokyo, Japan.

Oncostatin M (OSM) has been implicated in immune regulation, though its precise role remains elusive. Here we show that OSM plays a crucial role in the prevention of autoimmune diseases. OSM-deficient mice showed normal development of T cells, B cells and DC; however, their thymus showed hypoplasia and altered medullary structure. Autoantibodies against dsDNA accumulated and glomerulonephritis developed in aged OSM-deficient mice. Apoptotic cells accumulated in the thymus of OSM-deficient mice, and the administration of dexamethasone in young OSM-deficient mice resulted in the massive accumulation of apoptotic thymocytes and production of autoantibodies. These results suggest that OSM plays a key role in the prevention of autoimmune disease by regulating the clearance of apoptotic thymocytes.
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http://dx.doi.org/10.1002/eji.200839149DOI Listing
June 2009

Roundabout 4 is expressed on hematopoietic stem cells and potentially involved in the niche-mediated regulation of the side population phenotype.

Stem Cells 2009 Jan;27(1):183-90

Advanced Clinical Research Center, University of Tokyo, Japan.

Roundabout (Robo) family proteins are immunoglobulin-type cell surface receptors that are expressed predominantly in the nervous system. The fourth member of this family, Robo4, is distinct from the other family members in that it is expressed specifically in endothelial cells. In this study, we examined the expression of Robo4 in hematopoietic stem cells (HSCs) and its possible role in HSC regulation. Robo4 mRNA was specifically expressed in murine HSCs and the immature progenitor cell fraction but not in lineage-positive cells or differentiated progenitors. Moreover, flow cytometry showed a correlation between higher expression of Robo4 and immature phenotypes of hematopoietic cells. Robo4(high) hematopoietic stem/progenitor cells presented higher clonogenic activity or long-term repopulating activity by colony assays or transplantation assays, respectively. A ligand for Robo4, Slit2, is specifically expressed in bone marrow stromal cells, and its expression was induced in osteoblasts in response to myelosuppressive stress. Interestingly, overexpression of Robo4 or Slit2 in HSCs resulted in their decreased residence in the c-Kit(+)Sca-1(+)Lineage(-)-side population fraction. These results indicate that Robo4 is expressed in HSCs, and Robo4/Slit2 signaling may play a role in HSC homeostasis in the bone marrow niche.
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http://dx.doi.org/10.1634/stemcells.2008-0292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2883560PMC
January 2009

Expression of kin of irregular chiasm-like 3/mKirre in proprioceptive neurons of the dorsal root ganglia and its interaction with nephrin in muscle spindles.

J Comp Neurol 2008 Nov;511(1):92-108

Department of Anatomy & Neurobiology, Wakayama Medical University, Wakayama, Japan.

Kin of irregular chiasm-like 3 (Kirrel3), a mammalian homolog of the kirre gene of Drosophila melanogaster, belongs to the immunoglobulin superfamily. Previously, we have reported that Kirrel3 is expressed in the developing and adult central nervous system. In the present study we investigated the expression of Kirrel3 in the mouse dorsal root ganglia (DRG) and their projection targets. In the adult DRGs, Kirrel3 mRNA was detected in 21.5 +/- 2.3% of total DRG neurons and the expression was mainly prevalent in the medium- and large-sized neurons. In addition, Kirrel3 mRNA predominantly colocalized with tyrosine kinase receptor (Trk) C-immunoreactivity. In the developing DRGs, Kirrel3 mRNA was first detected in a few cells at embryonic day (E) 11.5, gradually increased, and reached the adult level at E17.5. During the development, Kirrel3 was expressed in most TrkC-positive DRG neurons. The expression of Kirrel3 was observed in TrkC-positive nerve fibers around neurotrophin 3 (NT3)-positive intrafusal muscle fibers of muscle spindles at E17.5. However, Kirrel3 was not expressed in TrkC-positive nerve fibers projecting to the spinal cord throughout development. Furthermore, nephrin was expressed in the NT3-positive intrafusal muscle fibers and was in close apposition with Kirrel3-immunoreactivity. Coimmunoprecipitation assay revealed that nephrin interacted with Kirrel3 in the developing muscles. These results suggest that Kirrel3 might play a role in the axonal pathfinding, cell recognition, and synapse formation of DRG neurons on appropriate target cells, including the targeting of proprioceptive neurons on muscle spindles through the interaction with nephrin.
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http://dx.doi.org/10.1002/cne.21838DOI Listing
November 2008

TROY, a novel member of the tumor necrosis factor receptor superfamily in the central nervous system.

Ann N Y Acad Sci 2008 Apr;1126:A1-10

Department of Anatomy and Neurobiology, Wakayama Medical University, Wakayama 641-8509, Japan.

Using a signal sequence trap method, we isolated TROY, a novel member of the tumor necrosis factor receptor superfamily (TNFRSF), from a mouse brain cDNA library. TROY mRNA is strongly expressed in brain and embryo. In situ hybridization analysis of the embryo showed that TROY mRNA was exclusively expressed in the epithelium of many tissues, including neuroepithelium. In the developing central nervous system, TROY mRNA was strongly expressed in the ventricular and subventricular zones, which contain neuronal and glial precursors during mouse embryogenesis that are both region-specific and stagedependent. In addition, TROY mRNA was expressed in the developing olfactory bulb from embryonic day (E) 13.5 to neonate. Next, we focused on the detailed cellular characterization of TROY-expressing cells in the developing olfactory system.TROYmRNAwas first detected in the olfactory nerve layer (ONL) of the olfactory bulb at E13.5 and was expressed most intensely in the inner ONL (ONL-i) during late embryogenesis. In the postnatal olfactory bulb, TROY-expressing cells were also detected in the glomerular layer (GL) and ONL-i. TROY was intensely expressed in olfactory ensheathing cells (OECs) of the ONL-i, which are positive for neuropeptide Y (NPY), but negative for S-100 or p75 low-affinity nerve growth factor receptor. Furthermore, TROY was also detected in glial fibrillary acidic protein (GFAP)-positive glial cells of the ONL-i and GL. Thus, TROY was expressed in some specific subsets of glial cells in the olfactory bulb, including OECs, and may play some roles in the developing and adult olfactory system.
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April 2008

Characterization of TROY/TNFRSF19/TAJ-expressing cells in the adult mouse forebrain.

Brain Res 2006 Sep 25;1110(1):81-94. Epub 2006 Jul 25.

Department of Anatomy and Neurobiology, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan.

A member of the tumor necrosis factor receptor superfamily (TNFRSF), TROY/TNFRSF19/TAJ, is highly expressed in the brain of adult mice. Northern blot analysis using mRNA taken from regions of the adult CNS showed the expression of TROY in all regions examined, including the olfactory bulb, cerebral cortex, striatum, and hippocampus. In situ hybridization and immunohistochemistry revealed that TROY mRNA and protein were strongly expressed in the rostral migratory stream (RMS) and subventricular zone (SVZ) of adult mice. In the adult SVZ, some glial fibrillary acidic protein (GFAP)-positive cells (type B cells) are thought to be multipotent neural stem cells. These type B cells divide slowly and generate epidermal growth factor receptor (EGFR)-positive transit-amplifying precursor cells (type C cells) in the presence of epidermal growth factor (EGF). Type C cells give rise to neuron-specific class III beta-tubulin (TuJ1)-positive neuroblasts (type A cells) that migrate to the olfactory bulb along the RMS. TROY-expressing cells were GFAP-positive, EGFR-positive, and TuJ1-negative in the adult SVZ. From these findings, TROY appears to be expressed in type B and type C cells, but not in type A cells, which was supported by immunoelectron microscopy. In addition, TROY was expressed in GFAP-positive astrocytes of the various regions, such as the cerebral cortex, striatum, and hippocampus. Thus, TROY was expressed in uncommitted precursor cells and astroglial lineage cells, suggesting that TROY plays some roles in the regulation of gliogenesis in the adult CNS.
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http://dx.doi.org/10.1016/j.brainres.2006.06.068DOI Listing
September 2006

Characterization of TROY-expressing cells in the developing and postnatal CNS: the possible role in neuronal and glial cell development.

Eur J Neurosci 2006 Jun;23(12):3149-60

Department of Anatomy and Neurobiology, Wakayama Medical University, 811-1, Kimiidera, Wakayama 641-8509, Japan.

A member of the tumor necrosis factor receptor superfamily, TROY, is expressed in the CNS of embryonic and adult mice. In the present study, we characterized TROY-expressing cells in the embryonic and postnatal forebrain. In the early embryonic forebrain, TROY was highly expressed in nestin-positive neuroepithelial cells and radial glial cells, but not in microtubule-associated protein 2-positive postmitotic neurons. During the late embryonic and postnatal development, expression of TROY was observed in radial glial cells and astrocytes, whereas its expression was not detected in neuronal lineage cells. In addition, TROY was exclusively expressed in Musashi-1-positive multipotent/glial progenitors in the postnatal subventricular zone. To investigate the functions of TROY in neural development, we overexpressed TROY in PC12 cells and established stably expressing cell clones. As expected, the signals from overexpressed TROY were constitutively transduced via the activation of the nuclear factor-kappaB and the c-Jun N-terminal kinase pathways in such clones. In addition, upregulation of negative basic helix-loop-helix transcription factors, HES-5 and Id2 proteins, was observed in the TROY-overexpressing clones. Interestingly, the overexpression of TROY in PC12 cells strongly inhibited nerve growth factor-induced neurite outgrowth with reduction of some markers of differentiated neurons, such as neurofilament 150 kDa and neuron-specific beta-tubulin. These findings suggest that the signaling from TROY regulates neuronal differentiation at least in part.
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http://dx.doi.org/10.1111/j.1460-9568.2006.04851.xDOI Listing
June 2006

Tumor rejection by the poliovirus receptor family ligands of the DNAM-1 (CD226) receptor.

Blood 2006 Feb 25;107(4):1491-6. Epub 2005 Oct 25.

Department of Immunology, Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1, Ten-nodai, Tsukuba, Ibaraki 305-8575, Japan.

The poliovirus receptor CD155 and its family member CD112 (nectin-2) are the ligands for the activating cell-surface receptor DNAM-1 on CD8+ T cells and natural killer (NK) cells. Here, we demonstrate that, whereas the RMA tumor grew in syngeneic mice, DNAM-1 ligand-transduced RMA was rejected, in which CD8+ T cells and NK cells played an essential role. Importantly, CD8+ memory cytotoxic T cells to parental RMA were generated in these mice. We found that DNAM-1 was also expressed on CD8alpha+, rather than CD8alpha-, dendritic cells (DCs). Cross-linking DNAM-1 induced maturation of CD8alpha+ DCs. Antigen presentation by these stimulated DCs drove Th1 cells. Moreover, the rejection of DNAM-1 ligand-transduced RMA was canceled in CD4+ T-cell-depleted and major histocompatibility complex class II-deficient mice. Taken together, these results suggest that DNAM-1 ligands stimulate innate immunity by CD8alpha+ DCs as well as NK cells, which efficiently prime cell-mediated tumor-specific immunity.
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http://dx.doi.org/10.1182/blood-2005-04-1684DOI Listing
February 2006

Infertility with defective spermiogenesis in mice lacking AF5q31, the target of chromosomal translocation in human infant leukemia.

Mol Cell Biol 2005 Aug;25(15):6834-45

Institute of Medical Science Division of Hematopoietic Factors, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

AF5q31 (also called MCEF) was identified by its involvement in chromosomal translocation with the gene MLL (mixed lineage leukemia), which is associated with infant acute lymphoblastic leukemia. Several potential roles have been proposed for AF5q31 and other family genes, but the specific requirements of AF5q31 during development remain unclear. Here, we show that AF5q31 is essential for spermatogenesis. Although most AF5q31-deficient mice died in utero and neonatally with impaired embryonic development and shrunken alveoli, respectively, 13% of AF5q31-deficient mice thrived as wild-type mice did. However, the male mice were sterile with azoospermia. Histological examinations revealed the arrest of germ cell development at the stage of spermiogenesis, and virtually no spermatozoa were seen in the epididymis. AF5q31 was found to be preferentially expressed in Sertoli cells. Furthermore, mutant mice displayed severely impaired expression of protamine 1, protamine 2, and transition protein 2, which are indispensable to compact the haploid genome within the sperm head, and an increase of apoptotic cells in seminiferous tubules. Thus, AF5q31 seems to function as a transcriptional regulator in testicular somatic cells and is essential for male germ cell differentiation and survival. These results may have clinical implications in the understanding of human male infertility.
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http://dx.doi.org/10.1128/MCB.25.15.6834-6845.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1190320PMC
August 2005

Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly.

Neurosci Res 2005 Oct;53(2):129-39

Department of Anatomy and Neurobiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama 641-8509, Japan.

Daily restraint for 3 weeks was shown to atrophy dendrites of hippocampal pyramidal neurons in rats. Brain-derived neurotrophic factor (BDNF), which maintains neuronal survival and morphology, has been shown to decrease in response to acute stress. Plasma glucocorticoid (GC) and serotonergic projections from the raphe nuclei play major roles in reducing BDNF synthesis in the hippocampus. We investigated BDNF mRNA levels there, together with plasma GC levels, GC receptors in the hippocampus/hypothalamus and 5-HT synthesizing enzyme, tryptophan hydroxylase in the raphe nuclei, in animals chronically stressed for 1-3 weeks, using in situ hybridization and immunohistochemistry. In these animals, BDNF mRNA levels were significantly decreased in the hippocampus after 6 h of restraint, but the ability of restraint to reduce BDNF synthesis seemed less robust than that seen in acute stress models. HPA axis response to stress in these animals assessed by plasma GC levels was delayed and sustained, and the GC receptor in the paraventricular hypothalamic nucleus was increased at 1 week. Tryptophan hydroxylase immunoreactivity was increased in the median raphe nucleus at 2-3 weeks. Repetitive stress-induced reduction of BDNF may partly contribute to the neuronal atrophy/death and reduction of hippocampal volume observed both in animals and humans suffering chronic stress and/or depression.
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http://dx.doi.org/10.1016/j.neures.2005.06.008DOI Listing
October 2005

Subcellular localization of glucose transporter 4 in the hypothalamic arcuate nucleus of ob/ob mice under basal conditions.

Brain Res 2005 Jul;1049(1):34-42

Department of Anatomy and Neurobiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.

Glucose transporter (GLUT) 4 plays an important role in insulin-induced glucose uptake in skeletal muscle and white adipose tissue. Although GLUT4 is abundant in the hypothalamus as well as in these peripheral tissues, little is known about the role of GLUT4 in the hypothalamus. In this study, we examined the subcellular localization of GLUT4 and the activation of insulin signaling pathways in the hypothalamic arcuate nucleus of ob/ob mice under basal conditions. The expression of GLUT4 in the arcuate nucleus of ob/ob mice was higher than that in lean mice. Interestingly, GLUT4 on the plasma membrane increased significantly in neurons of the arcuate nucleus of ob/ob mice when compared to that in lean mice. Because serum insulin levels of ob/ob mice were very high, we hypothesized that insulin strongly stimulates GLUT4 translocation in the arcuate nucleus of ob/ob mice. Unexpectedly, tyrosine phosphorylation of IR and insulin receptor substrate-1 (IRS-1) was faint in the hypothalamus of lean and ob/ob mice. In addition, phosphorylation of IRS-1 at Ser307 in the hypothalamus of ob/ob mice was higher when compared to that in lean mice, suggesting that insulin signaling is impaired by phosphorylation of IRS-1 at Ser307 in the hypothalamus of ob/ob mice. However, serine phosphorylation of Akt in the arcuate nucleus of ob/ob mice increased significantly when compared to that in lean mice. Furthermore, the expression of brain-derived neurotrophic factor, an activator of PI3K-Akt pathway in neurons, increased significantly in the ventromedial hypothalamus of ob/ob mice. We discuss the possibility of novel pathways which induce the translocation of GLUT4 in the arcuate nucleus of ob/ob mice.
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http://dx.doi.org/10.1016/j.brainres.2005.04.079DOI Listing
July 2005

Neuronal leucine-rich repeat protein 4 functions in hippocampus-dependent long-lasting memory.

Mol Cell Biol 2005 May;25(10):4166-75

Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.

Neuronal leucine-rich repeat proteins (NLRRs) are type I transmembrane proteins and expressed in neuronal tissues, but their function remains unknown. Here, we describe the identification and characterization of a new member of the NLRR family, NLRR4, and its potential role in long-lasting memory. We generated NLRR4-deficient (NLRR4(-/-)) mice and found that they showed impaired memory retention. In hippocampus-dependent learning tasks, NLRR4(-/-) mice were able to learn and maintain the memories for one day but unable to retain the memories for four days after learning. In contrast, in a hippocampus-independent task, NLRR4(-/-) mice were able to retain the memory normally for at least seven days. These results suggest that NLRR4 plays a key role in hippocampus-dependent long-lasting memory.
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http://dx.doi.org/10.1128/MCB.25.10.4166-4175.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1087730PMC
May 2005

Oncostatin M in the development of the nervous system.

Anat Sci Int 2005 Mar;80(1):53-9

Department of Anatomy and Neurobiology, Wakayama Medical University, Wakayama, Japan.

Oncostatin M (OSM) is a member of the interleukin-6 family of cytokines. Of these cytokines, OSM is closely related structually, genetically and functionally to leukemia inhibitory factor. However, OSM-specific biological activities have been reported in hematopoiesis and liver development. Recently, we have demonstrated OSM-specific activities in the nervous systems. In the adult central nervous system (CNS), OSM receptor (OSMR) beta was observed in meningeal cells of pia mater, epithelial cells of the choroid plexus and olfactory astrocyte-like glia surrounding the glomeruli of the olfactory bulb. In the CNS of neonatal mice, OSMRbeta was also expressed in the ventral subnucleus of the hypoglossal nucleus, but disappeared at post-natal day (P) 14. In contrast with the CNS, OSMRbeta was strongly expressed in small-sized non-peptidergic neurons of the dorsal root ganglia (DRG) and trigeminal ganglia (TG). Interestingly, all OSMRbeta-positive neurons in these ganglia also expressed both TRPV1 (a vanilloid receptor) and P2X3 (a purinergic receptor). In OSM-deficient mice, TRPV1/P2X3/OSMRbeta triple-positive neurons were significantly decreased. Consistent with such histological findings, OSM-deficient mice exhibited a reduction in responses to various stimuli, including mechanical and thermal stimuli. These findings suggest an important role for OSM in the development of a subset of nociceptive neurons.
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http://dx.doi.org/10.1111/j.1447-073x.2005.00100.xDOI Listing
March 2005

Attenuation of fasting-induced phosphorylation of mitogen-activated protein kinases (ERK/p38) in the mouse hypothalamus in response to refeeding.

Neurosci Lett 2004 Nov;371(1):40-4

Department of Anatomy and Neurobiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.

Nutritional status modify the expression of hypothalamic neuropeptides through various signal molecules, including mitogen-activated protein kinases (MAPKs) and cAMP/calcium-responsive element-binding protein (CREB), for the regulation of energy balance. Previously, we demonstrated fasting-induced activation of extracellular signal-regulated kinase 1/2 (ERK) and p38 mitogen-activated protein kinase (p38) in the murine hypothalamus. To study how caloric intake after food deprivation influences intracellular signal transduction, we investigated the phosphorylation of ERK and p38 in the murine hypothalamus of refed mice. In the arcuate nucleus, refeeding significantly attenuated fasting-induced phosphorylation of ERK and CREB. In the paraventricular nucleus, fasting-induced phosphorylation of ERK and p38 was also significantly decreased by refeeding. Thus, refeeding rapidly reduced the fasting-induced phosphorylation of ERK, p38, and CREB, suggesting that the activation of these signal molecules in the hypothalamus is precisely regulated with feeding status.
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http://dx.doi.org/10.1016/j.neulet.2004.08.035DOI Listing
November 2004