Role of an alternatively spliced nuclear variant of ErbB3 in the nervous system

ErbB3 的选择性剪接核变体在神经系统中的作用

• 批准号: 8643827
• 负责人: Nikolaos Tapinos
• 金额: $ 34.25万
• 依托单位: GEISINGER CLINIC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8643827
• 关键词: Affect; Affinity; Alternative Splicing; Attenuated; Axon; Binding; Biological Assay; Cell Extracts; Cell Nucleus; Cell physiology; Cells; ChIP-on-chip; Chromatin; Co-Immunoprecipitations; Computer Analysis; Cytoplasmic Tail; DNA Binding; Data; Development; Electrophoretic Mobility Shift Assay; Elements; Epidermal Growth Factor Receptor; ErbB4 gene; Event; Exhibits; Family; Gene Expression; Gene Expression Profiling; Gene Targeting; Genes; Goals; Injury; Length; Ligands; Luciferases; Mass Spectrum Analysis; Mediating; Membrane; Molecular; Myelin; Nervous system structure; Neuraxis; Neuregulin 1; Neuregulins; Neuroglia; Neurons; Nuclear; Nuclear Localization Signal; Pathogenesis; Peptide Signal Sequences; Peripheral; Peripheral Nervous System; Peripheral Nervous System Diseases; Phosphotransferases; Play; Protein Binding; Proteins; Protocols documentation; RNA Splicing; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Recombinants; Recovery of Function; Regulation; Role; Schwann Cells; Signal Transduction; Sorting - Cell Movement; Testing; Transcriptional Regulation; Variant; base; design; member; myelination; nervous system development; novel; promoter; public health relevance; receptor; research study; response; therapy development; transcription factor

DESCRIPTION (provided by applicant): ErbB3 receptor tyrosine kinase (RTK) and its associated signaling regulate the development, maturation and function of the peripheral nervous system (PNS). Here we describe a new alternatively spliced ErbB3 variant (nuc-ErbB3) that is localized in the nucleus of Schwann cells (the glial cells of the PNS). Based on our preliminary data, nuc-ErbB3 controls proper axon recognition, axonal sorting and myelination by Schwann cells independent of the full-length ErbB3 receptor. nuc- ErbB3 possesses a functional nuclear localization signal sequence and binds to transcriptionally active chromatin. Using ChIP-ChIP arrays we identified the gene promoters that interact with nuc- ErbB3 and clustered the active promoters in Schwann cell gene expression. Our long-term objective is to elucidate the function of nuc-ErbB3 as a transcription factor and understand its role during the establishment of Schwann cell neuron interactions and myelination. Specifically, we aim to: 1. Determine the functional significance of nuc-ErbB3 in the establishment of axon-glial interactions and myelination, 2. Reveal the role of nuc-ErbB3 as a transcriptional regulator that influences the interaction of Schwann cells with axons and 3. Identify protein-binding partners of nuc-ErbB3 in the nucleus of Schwann cells and determine how they modulate nuc-ErbB3 function. We believe that the accomplishment of these aims will reveal a new concept for membrane receptor tyrosine kinase regulation of cellular processes in the nervous system through their alternatively spliced nuclear variants. Moreover, exploration of the transcriptional role of nuc-ErbB3 and its function during axon-glial interactions and myelination will provide useful information in relation to peripheral neuropathies caused by deregulated gene expression and/or altered myelin formation.

描述（由申请人提供）：ErbB3受体酪氨酸激酶（RTK）及其相关信号传导调节外周神经系统（PNS）的发育、成熟和功能。在这里，我们描述了一个新的选择性剪接的ErbB3变体（nuc-ErbB3），它位于雪旺细胞（神经胶质细胞的PNS）的细胞核中。基于我们的初步数据，nuc-ErbB3控制适当的轴突识别，轴突分选和髓鞘形成的雪旺细胞独立于全长ErbB3受体。nuc-ErbB3具有功能性核定位信号序列并结合转录活性染色质。使用ChIP-ChIP阵列，我们鉴定了与nuc-ErbB3相互作用的基因启动子，并将雪旺细胞基因表达中的活性启动子聚类。我们的长期目标是阐明nuc-ErbB3作为转录因子的功能，并了解其在雪旺细胞神经元相互作用和髓鞘形成过程中的作用。具体而言，我们的目标是：1。确定nuc-ErbB3在建立轴突-胶质细胞相互作用和髓鞘形成中的功能意义，2.揭示nuc-ErbB3作为影响雪旺细胞与轴突相互作用的转录调节因子的作用，3.确定雪旺细胞核中nuc-ErbB3的蛋白结合伴侣，并确定它们如何调节nuc-ErbB3功能。我们相信，这些目标的实现将揭示一个新的概念，膜受体酪氨酸激酶调节细胞过程中的神经系统通过其选择性剪接的核变体。此外，探索nuc-ErbB3的转录作用及其在轴突-胶质细胞相互作用和髓鞘形成过程中的功能，将提供与由基因表达失调和/或髓鞘形成改变引起的周围神经病变相关的有用信息。

项目成果

Nuc-ErbB3 regulates H3K27me3 levels and HMT activity to establish epigenetic repression during peripheral myelination.

• DOI: 10.1002/glia.22977
• 发表时间: 2016-06
• 期刊: GLIA
• 影响因子: 6.2
• 作者: Ness, Jennifer K.;Skiles, Amanda A.;Yap, Eng-Hui;Fajardo, Eduardo J.;Fiser, Andras;Tapinos, Nikos
• 通讯作者: Tapinos, Nikos

A nuclear variant of ErbB3 receptor tyrosine kinase regulates ezrin distribution and Schwann cell myelination.

• DOI: 10.1523/jneurosci.5635-10.2011
• 发表时间: 2011-03-30
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Adilakshmi T;Ness-Myers J;Madrid-Aliste C;Fiser A;Tapinos N
• 通讯作者: Tapinos N

Regulation of Peripheral Myelination through Transcriptional Buffering of Egr2 by an Antisense Long Non-coding RNA.

• DOI: 10.1016/j.celrep.2017.07.068
• 发表时间: 2017-08-22
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Martinez-Moreno M;O'Shea TM;Zepecki JP;Olaru A;Ness JK;Langer R;Tapinos N
• 通讯作者: Tapinos N