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

描述（由申请人提供）：ErbB 3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ErbB 3变体（nuc-ErbB 3），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-ErbB 3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ErbB 3受体。nuc-ErbB 3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-ErbB 3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-ErbB 3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-ErbB 3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-ErbB 3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-ErbB 3的蛋白结合伴侣，并确定它们如何调节nuc-ErbB 3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-ErbB 3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。 公共卫生相关性：脊椎动物神经系统中神经胶质细胞与轴突最初相互作用的分子基础事件知之甚少。然而，这些事件决定了神经系统的正常发育以及损伤后髓鞘形成和功能恢复的程度。在外周神经系统（PNS）中，施万细胞的增殖、髓鞘形成和髓鞘再形成的主要调节剂是神经调节蛋白/ErbB 2 -3受体信号传导。在我们的建议中，我们描述了一个核变异的ErbB 3受体酪氨酸激酶（nuc-ErbB 3），是由选择性剪接。我们认为nuc-ErbB 3的作用是非常重要的，建立适当的轴突-神经胶质细胞的相互作用和髓鞘形成的PNS，随后，我们提出实验来研究nuc-ErbB 3作为雪旺细胞反应的转录调节因子的作用。

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. PUBLIC HEALTH RELEVANCE: The molecular events underlying the initial interaction of glial cells with axons in the vertebrate nervous system are poorly understood. However, these events determine the proper development of the nervous system and the extent of myelination and functional recovery following injury. In the peripheral nervous system (PNS), the predominant regulator of proliferation, myelination and re- myelination by Schwann cells is neuregulin/ErbB2-3 receptor signaling. In our proposal we describe a nuclear variant of ErbB3 receptor tyrosine kinase (nuc-ErbB3) that is produced by alternative splicing. We believe the role of nuc-ErbB3 is very important for the establishment of proper axon-glial interactions and myelination in the PNS and subsequently we propose experiments to study the role of nuc-ErbB3 as a transcriptional regulator of Schwann cell responses.