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

描述(申请人提供)：erbB3受体酪氨酸激酶(RTK)及其相关信号调节周围神经系统(PNS)的发育、成熟和功能。在这里，我们描述了一种新的可选择性剪接的ErbB3变异体(nuc-ErbB3)，它定位于雪旺细胞(PNS的胶质细胞)的细胞核中。根据我们的初步数据，nuc-ErbB3独立于全长ErbB3受体，控制雪旺细胞正确的轴突识别、轴突分类和髓鞘形成。Nuc-ErbB3具有功能性核定位信号序列，并与转录活性染色质结合。利用芯片芯片阵列，我们鉴定了与nuc-ErbB3相互作用的基因启动子，并对雪旺细胞基因表达中的活性启动子进行了聚类。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中的作用。具体地说，我们的目标是：1.确定nuc-ErbB3在建立轴突-神经胶质相互作用和髓鞘形成中的功能意义；2.揭示nuc-ErbB3作为转录调节因子影响雪旺细胞与轴突相互作用的作用；3.在雪旺细胞核中鉴定nuc-ErbB3的蛋白结合伙伴，并确定它们是如何调节Nuc-ErbB3功能的。我们相信，这些目标的实现将揭示膜受体酪氨酸激酶通过其选择性剪接的核变异体来调节神经系统中的细胞过程的新概念。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作用，将为周围神经疾病提供有用的信息，这些疾病是由基因表达失调和/或髓鞘形成改变引起的。 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。在周围神经系统(PNS)中，神经调节蛋白/ErbB2-3受体信号是雪旺细胞增殖、髓鞘形成和再髓鞘形成的主要调节因子。在我们的建议中，我们描述了一种ErbB3受体酪氨酸激酶的核变体(nuc-ErbB3)，它是通过选择性剪接产生的。我们认为nuc-ErbB3的作用对于在三叉神经节中建立适当的轴突-神经胶质相互作用和髓鞘形成是非常重要的，随后我们提出了实验来研究nuc-ErbB3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.