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Semaphorin-1a acts in concert with the cell adhesion molecules fasciclin II and connectin to regulate axon fasciculation in Drosophila

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GENETICS 2000年第2期156卷 723-731页

作者： Yu, HH Huang, AS Kolodkin, AL Johns Hopkins Univ Sch Med Dept Neurosci Baltimore MD 21205 USA

Semaphorins comprise a large family of phylogenetically conserved secreted and transmembrane glycoproteins, many of which have been implicated in repulsive axon guidance events. The transmembrane semaphorin Sema-1a in Drosophila is expressed on motor axone and is required for the generation of neuromuscular connectivity. Sema-1a can function as an axonal repellent and mediates motor axon defasciculation. Here, by manipulating the levels of Sema-1a and the cell adhesion molecules fasciclin II (Fas II) and connectin (Conn) on motor axons, we provide further evidence that Sema-1a mediates axonal defasciculation events by acting as an axonally localized repellent and that correct motor axon guidance results from a balance between attractive and repulsive guidance cues expressed on motor neurons.

关键词：动物基因修饰轴突/生理学细胞黏附分子/遗传学细胞黏附分子/生理学细胞黏附分子神经元/遗传学细胞黏附分子神经元/生理学交叉遗传果蝇黑腹/遗传学果蝇黑腹/生理学肌束震颤基因型糖蛋白类/遗传学糖蛋白类/生理学肌蛋白质类/遗传学肌蛋白质类/生理学神经生长因子类/遗传学神经生长因子类/生理学蛋白激酶类/遗传学蛋白激酶类/生理学信号素3A 动物女(雌)性男(雄)性

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Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第3期97卷 1230-1235页

作者： Bai, C Connolly, B Metzker, ML Hilliard, CA Liu, XM Sandig, V Soderman, A Galloway, SM Liu, QY Austin, CP Caskey, CT Merck Res Labs Dept Human Genet West Point PA 19486 USA Merck Res Labs Dept Genet & Cellular Toxicol West Point PA 19486 USA

Fas-mediated apoptosis is an important regulator of cell survival, and abnormalities in this system have been shown to result in a number of human pathological conditions. A secreted member of the tumor necrosis factor receptor superfamily, DcR3, was recently reported to be amplified in human lung and colon cancers as a negative regulator of Fas-mediated apoptosis. We identified this gene, which we call M68. M68 genomic DNA, mRNA, and protein levels were examined in a series of human gastrointestinal tract tumors. Using M68 immunohistochemistry and a scoring system similar to that used for HER-2/neu, we found that M68 protein was overexpressed in 30 of 68 (44%) human adenocarcinomas of the esophagus, stomach, colon, and rectum. Tumors examined by Northern blot revealed M68 mRNA highly elevated in a similar fraction of primary tumors from the same gastrointestinal tract regions, as well as in the colon adenocarcinoma cell lines SW480 and SW1116. Further, we found M68 protein to be overexpressed in a substantial number of tumors in which gene amplification could not be detected by fluorescence in situ hybridization or quantitative genomic PCR, suggesting that overexpression of M68 may precede amplification in tumors. Finally, we find that M68 lies within a four-gene cluster that includes a novel helicase-like gene (NHL) related to RAD3/ERCC2, a plasma membrane Ras-related GTPase and a member of the stathmin family, amplification or overexpression of which may also contribute to cell growth and tumor progression.

关键词： ADP核糖基化因子氨基酸序列细胞凋亡染色体图染色体人 20对/遗传学 DNA解旋酶类/遗传学 DNA 互补/遗传学食管肿瘤/遗传学表达的序列标记 GTP磷酸水解酶类/遗传学胃肠肿瘤/遗传学基因扩增基因表达调控肿瘤基因膜糖蛋白类膜蛋白质类/遗传学分子序列数据肿瘤蛋白质类/生物合成肿瘤蛋白质类/遗传学神经生长因子类/遗传学聚合酶链反应 RNA 信使/生物合成 RNA 肿瘤/遗传学受体细胞表面/生物合成受体细胞表面/遗传学受体肿瘤坏死因子受体肿瘤坏死因子成员6b 序列比对序列同源性氨基酸癌蛋白18 人类

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Activation of the Stat3 signaling pathway is required for differentiation by interleukin-6 in PC12-E2 cells

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第3期275卷 2147-2156页

作者： Wu, YY Bradshaw, RA Univ Calif Irvine Coll Med Dept Anat & Neurobiol Irvine CA 92697 USA Univ Calif Irvine Coll Med Dept Physiol & Biophys Irvine CA 92697 USA

The role of signal transducer and activator of transcription (STAT) signaling pathways in the interleukin-6 (IL-6)-induced morphological differentiation of PC12-E2 cells was assessed using wild type and dominant negative mutants of Stat1 and Stat3, containing Tyr --> Phe (YF), Ser --> Ala (SA), and the double mutations (DM), respectively. FS3-YF or FS3-DM markedly inhibited the IL-6-induced response, but overexpression of FS3-SA caused only a modest inhibition. Expression of all Stat3 mutants had no effect on NGF-induced neurite outgrowth. Overexpression of wild type Stat1 protein inhibited IL-6 activated DNA binding complexes containing Stat3 homodimers, which may explain the partial negative effect of Stat1 on IL-6-induced neurite outgrowth. Specificity of these STAT constructs was confirmed using luciferase reporter gene assays, which showed that IL-6-activated transcription was blocked by expression of FS3-YF and FS3-DM and that FS1 enhanced the interferon gamma-activated transcription. Thus, in PC12-E2 cells, Stat3 homodimers are preferentially activated by IL-6, indicating a role for Stat3 in the regulation of cellular differentiation. Furthermore, IL-6 induced robust neurite outgrowth in PC12-E2 cells expressing dominant negative forms of RAS or SHC or in cells pretreated with the mitogen-activated protein kinase mitogen-activated protein kinase kinase inhibitor, PD98059, Thus, activation of the Stat3 signaling pathway, but not RAS/ERK dependent pathways, is essential for differentiation of PC12-E2 cells by IL-6.

关键词：衔接蛋白质类信号转导衔接蛋白质类膜泡运输细胞分化/生理学细胞系 DNA结合蛋白质类/遗传学 DNA结合蛋白质类/代谢剂量效应关系药物酶抑制剂/药理学类黄酮物质/药理学基因表达调控基因显性干扰素γ/代谢白细胞介素6/代谢诱变定点神经生长因子类/遗传学神经生长因子类/代谢神经突/代谢 PC12细胞磷酰化蛋白质类/遗传学蛋白质类/代谢原癌基因蛋白质p21(ras)/遗传学原癌基因蛋白质p21(ras)/代谢 STAT1转录因子 STAT3转录因子丝氨酸/代谢 Shc信号衔接蛋白质类信号传导时间因素反式激活因子类/遗传学反式激活因子类/代谢酪氨酸/代谢动物人类大鼠

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Role of neurotropins in rat embryonic testis morphogenesis (cord formation)

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BIOLOGY OF REPRODUCTION 2000年第1期62卷 132-142页

作者： Levine, E Cupp, AS Skinner, MK Washington State Univ Dept Genet & Cell Biol Ctr Reprod Biol Pullman WA 99164 USA

The process of seminiferous cord formation is the first morphological event that differentiates a testis from an ovary and indicates male sex determination. Cord formation occurs by embryonic Day 14 (Day 0 plug date;E14) in the rat. A series of experiments were conducted to determine if neurotropins and their receptors are important for the process of rat embryonic cord formation. The expression of low affinity neurotropin receptor (p75/LNGFR) was determined by immunohistochemistry on sections of both testis and ovary from E13 through birth (Day 0, PO) with an antibody to p75/LNGFR, The staining for p75/LNGFR was present in the mesonephros of E13 gonads and in a sex-specific manner appeared around developing cords at E14 in the embryonic testis. At birth, staining for p75/LNGFR was localized to a single layer of cells (i.e., peritubular cells) that surrounded the seminiferous cords. The genes for both neurotropin 3 (NT3) and for corresponding high affinity neurotropin trkC receptor were found to be expressed in the E14 rat testis, as well as other neurotropins and receptors. Immunocytochemical analysis of E14 rat testis demonstrated that NT3 was localized to the Sertoli cells and trkC was present in individual cells of the interstitium at E16 and in selected preperitubular cells at E18. Previously, the peritubular cells adjacent to the cords were demonstrated to be derived from migrating mesonephros cells around the time of cord formation. To determine if neurotropins were involved in cord formation, the actions of neurotropins were inhibited. A high affinity neurotropin receptor (trk)-specific kinase inhibitor, K252a, was used to treat organ cultures of testes from E13 rats prior to cord formation. Treatment of E13 testis organ cultures with K252a completely inhibited cord formation. K252a-treated organ cultures of E14 testis that contained cords did not alter cord morphology. A second experiment to inhibit neurotropin actions utilized a specific antagonist trk-IgG

关键词：基因表达孕龄免疫组织化学小鼠基因敲除形态发生神经生长因子类/遗传学神经生长因子类/生理学神经营养因子3/分析神经营养因子3/遗传学器官培养技术卵巢/胚胎学大鼠 Sprague-Dawley 受体 trkC/分析受体 trkC/遗传学塞尔托利细胞/化学睾丸/胚胎学动物女(雌)性男(雄)性小鼠妊娠大鼠

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Extension of long leading processes and neuronal migration in the mammalian brain directed by the chemoattractant netrin-1

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NEURON 1999年第3期24卷 607-622页

作者： Yee, KT Simon, HH Tessier-Lavigne, M O'Leary, DDM Salk Inst Biol Studies Mol Neurobiol Lab La Jolla CA 92037 USA Univ Calif San Francisco Howard Hughes Med Inst Dept Anat San Francisco CA 94143 USA Univ Calif San Francisco Howard Hughes Med Inst Dept Biochem & Biophys San Francisco CA 94143 USA

Long distance cell migration occurs throughout the developing CNS, but the underlying cellular and molecular mechanisms are poorly understood. We show that the directed circumferential migration of basilar pontine neurons from their origin in the neuroepithelium of the dorsal hindbrain to the ventral midline involves the extension of long (>1 mm) leading processes, which marker analyses suggest are molecularly distinct from axons. In vivo analysis of knockout mice implicates the axonal chemoattractant netrin-1, functioning via its receptor Deleted in Colorectal Cancer (DCC), in attracting the leading process to the ventral midline. Direct evidence for this chemoattractant mechanism is provided, using explant cultures and time-lapse analysis in vitro. Our results demonstrate the attraction of migrating neurons in the mammalian brain by an axon guidance molecule and the chemotactic responsiveness of their leading processes.

关键词：脑/细胞学脑/生理学细胞黏附分子/遗传学细胞黏附分子/代谢细胞黏附分子神经元细胞运动/生理学上皮细胞/生理学膜糖蛋白类/代谢小鼠基因敲除/遗传学神经生长因子类/遗传学神经生长因子类/生理学神经元/代谢神经元/生理学脑桥/细胞学脑桥/生理学大鼠 Sprague-Dawley 受体细胞表面菱脑/细胞学菱脑/生理学肿瘤抑制蛋白质类动物小鼠大鼠

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Estrogen-inducible, sex-specific expression of brain-derived neurotrophic factor mRNA in a forebrain song control nucleus of the juvenile zebra finch

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第14期96卷 8241-8246页

作者： Dittrich, F Feng, Y Metzdorf, R Gahr, M Vrije Univ Amsterdam Dept Dev Neurobiol Fac Biol NL-1081 HV Amsterdam Netherlands Max Planck Inst Verhaltensphysiol D-82319 Seewiesen Germany

The expression of brain-derived neurotrophic factor (BDNF) mRNA is increased significantly within the high vocal center (HVc) of male but not female zebra finches from posthatching day 30-35 on. The population of HVc cells expressing BDNF mRNA included 35% of the neurons projecting to the nucleus robustus of the archistriatum (RA). In the RA and in RA-projecting neurons of the lateral portion of the magnocellular nucleus of the anterior neostriatum, BDNF mRNA was expressed at very low levels in both sexes. The BDNF-receptor trkB mRNA was expressed in the RA, in RA-projecting neurons of lateral portion of the magnocellular nucleus of the anterior neostriatum, and in the HVc, except in most of its RA-projecting neurons. Premature stimulation and an inhibitory effect on the normal increase of the BDNF mRNA expression in juvenile males occurred after treatments with 17 beta-estradiol and the aromatase inhibitor fadrozole, respectively. The up-regulation of the BDNF expression in the HVc could be a mechanism by which estrogen triggers the differentiation of cells within and connected to the HVc of male zebra finches.

关键词：芳香酶抑制剂脑/代谢脑源性神经营养因子/遗传学药物植入物雌二醇/投药和剂量雌二醇/药理学法倔唑/药理学海马/药物作用海马/代谢原位杂交神经元/细胞学神经元/药物作用神经元/代谢前脑/药物作用前脑/代谢 RNA 信使/遗传学受体蛋白质酪氨酸激酶类/遗传学受体睫状神经营养因子受体神经生长因子类/遗传学性征鸣禽鸟/生理学转录遗传/药物作用转录遗传/生理学发声动物/生理学动物女(雌)性男(雄)性

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amos, a proneural gene for Drosophila olfactory sense organs that is regulated by lozenge

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NEURON 2000年第1期25卷 69-78页

作者： Goulding, SE zur Lage, P Jarman, AP Univ Edinburgh Inst Cell & Mol Biol Edinburgh EH9 3JR Midlothian Scotland

In a variety of organisms, early neurogenesis requires the function of basic-helix-loop-helix (bHLH) transcription factors. For the Drosophila PNS, such transcription factors are encoded by the proneural genes (atonal and the achaete-scute complex, AS-C). We have identified a proneural gene, amos, that has strong similarity with atonal in its bHLH domain. We present evidence that amos is required for olfactory sensilla and is regulated by the prepattern gene lozenge. Between them, amos, atonal, and the AS-C can potentially account for the origin of the entire PNS.

关键词：动物结构/细胞学动物结构/生长和发育碱性螺旋-环-螺旋转录因子类细胞分化/遗传学 DNA结合蛋白质类/化学 DNA结合蛋白质类/遗传学 DNA结合蛋白质类/代谢二聚作用果蝇属/遗传学果蝇属/代谢果蝇蛋白质类基因表达调控发育期螺旋-环-螺旋构型/遗传学昆虫蛋白质类/遗传学分子序列数据神经生长因子类/遗传学神经生长因子类/代谢神经组织蛋白质类核蛋白质类/代谢嗅通路/细胞学嗅通路/生长和发育嗅觉受体神经元/化学嗅觉受体神经元/细胞学嗅觉受体神经元/生理学周围神经系统/细胞学周围神经系统/生长和发育 RNA 信使/遗传学序列同源性氨基酸干细胞/化学干细胞/细胞学干细胞/生理学转录因子/遗传学转录因子/代谢动物男(雄)性

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Developmental profiles of growth-associated protein (Gap43), Ngfb, Bndf and Ntf4 mRNA levels in the rat forebrain after exposure to 60 Hz magnetic fields

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RADIATION RESEARCH 2000年第5期153卷 642-647页

作者： Harry, GJ Bartenbach, M Haines, W Bruccoleri, A NIEHS Neurotoxicol Grp Res Triangle Pk NC 27709 USA

Fischer 344 rats were exposed to 60 Hz magnetic fields (EMFs) during gestation and lactation. Rats received continuous exposure to 2-, 200- or 1000-mu T magnetic fields for 18.5 h per day, 7 days a week, or sham exposure (sham controls). During postnatal development, on postnatal days 1, 3, 6, 9, 15 and 20, forebrain tissue from male pups was examined for alterations in mRNA level for developmentally regulated central nervous system-specific proteins. Alterations in these factors during critical periods of development could result in alterations in the final neural network. Gap43 (growth-associated protein 43) mRNA was measured by Northern hybridization as a developmental indicator of axonal growth during the development of the neuron. Between postnatal days 1 and 9, detectable levels of Gap43 mRNA displayed a similar pattern across all sham control and exposure groups. In addition to Gap43, mRNA levels for the nervous system-specific growth factors ciliary neurotrophic factor (Cntf), brain-derived neurotrophic factor (Bdnf), beta nerve growth factor (Ngfb), neurotrophin-3 (Ntf3), and neurotrophin-4 (Ntf4) were examined by RNase protection assay. While there is public concern for developmental neurotoxicity associated with exposure to EMFs, these data, generated from animals exposed to 2-, 200 or 1000-mu T magnetic fields during both gestational and lactational periods of development, suggest that under these conditions no significant alterations in these critical factors for brain development occur. (C) 2000 by Radiation Research Society.

关键词：动物新生动物吮乳期脑源性神经营养因子/遗传学脑源性神经营养因子/代谢剂量效应关系辐射电磁场/副作用环境暴露/副作用 GAP-43蛋白/遗传学 GAP-43蛋白/代谢胶质细胞源性神经营养因子母亲暴露/副作用神经生长因子/遗传学神经生长因子/代谢神经生长因子类/遗传学神经生长因子类/代谢神经组织蛋白质类/遗传学神经组织蛋白质类/代谢神经营养因子3/遗传学神经营养因子3/代谢前脑/生长和发育前脑/代谢前脑/辐射效应 RNA 信使/分析大鼠近交F344 大鼠 Sprague-Dawley 核糖核酸酶类/代谢动物女(雌)性男(雄)性大鼠

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brakeless is required for photoreceptor growth-cone targeting in Drosophila

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第11期97卷 5966-5971页

作者： Rao, Y Pang, P Ruan, WJ Gunning, D Zipursky, SL McGill Univ Neurosci Res Ctr Dept Neurol & Neurosurg Montreal PQ H3G 1A4 Canada Montreal Gen Hosp Montreal PQ H3G 1A4 Canada Univ Calif Los Angeles Sch Med Dept Biol Chem Inst Mol Biol Los Angeles CA 90095 USA

The R1-R6 subclass of photoreceptor neurons (R cells) in the Drosophila compound eye form specific connections with targets in the optic ganglia, In this paper, we report the identification of a gene, brakeless (bks), that is essential for R1-R6 growth cone targeting. In brakeless mutants, R1-R6 growth cones frequently fail to terminate migration in their normal target, the lamina, and instead project through it and terminate in the second optic ganglion, the medulla, Genetic mosaic analysis and transgene rescue experiments indicate that bks functions in R cells and not within the lamina target region. bks encodes a nuclear protein. We propose that it participates in a gene expression pathway regulating one or more growth cone components controlling R1-R6 targeting.

关键词：氨基酸序列动物基因修饰细胞分化果蝇蛋白质类果蝇黑腹/遗传学果蝇黑腹/生长和发育眼/神经支配神经节无脊椎动物/细胞学生长锥/生理学昆虫蛋白质类/遗传学昆虫蛋白质类/生理学幼虫分子序列数据形态发生镶嵌现象神经生长因子类/遗传学神经生长因子类/生理学光感受器/细胞学光感受器/生理学视通路/生长和发育动物

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GFRα3, a component of the artemin receptor, is required for migration and survival of the superior cervical ganglion

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NEURON 1999年第4期23卷 725-736页

作者： Nishino, J Mochida, K Ohfuji, Y Shimazaki, T Meno, C Ohishi, S Matsuda, Y Fujii, H Saijoh, Y Hamada, H Osaka Univ Inst Mol & Cellular Biol Div Mol Biol Osaka Japan Japan Sci & Technol Corp Suita Osaka 5650871 Japan Tokyo Metropolitan Inst Med Sci Bunkyo Ku Tokyo 113 Japan Nagoya Univ Sch Agr Sci Lab Anim Genet Chikusa Ku Nagoya Aichi 4648601 Japan

GFR alpha 3 is a component of the receptor for the neurotrophic factor artemin. The role of GFR alpha 3 in nervous system development was examined by generating mice in which the Gfr alpha 3 gene was disrupted. The Gfr alpha 3(-/-) mice exhibited severe defects in the superior cervical ganglion (SCG), whereas other ganglia appeared normal. SCG precursor cells in the mutant embryos failed to migrate to the correct position, and they subsequently failed to innervate the target organs. In wildtype embryos, Gfr alpha 3 was expressed in migrating SCG precursors, and artemin was expressed in and near the SCG. After birth, SCG neurons in the mutant mice underwent progressive cell death. These observations suggest that GFR alpha 3-mediated signaling is required both for the rostral migration of SCG precursors and for the survival of mature SCG neurons.

关键词：细胞死亡/生理学细胞运动/遗传学细胞运动/生理学细胞存活/生理学果蝇蛋白质类基因型免疫组织化学原位杂交小鼠基因敲除神经生长因子类/代谢神经组织蛋白质类/代谢神经元/生理学原癌基因蛋白质类/遗传学原癌基因蛋白质类/生理学原癌基因蛋白质c-ret 受体蛋白质酪氨酸激酶类/遗传学受体蛋白质酪氨酸激酶类/生理学受体神经生长因子类/遗传学受体神经生长因子类/代谢颈上神经节/细胞学颈上神经节/胚胎学动物小鼠

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