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

描述（由申请人提供）：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选择性剪接ErbB3变体（nucc -ErbB3），它位于雪旺细胞（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，控制着雪旺细胞正确的轴突识别、轴突分选和髓鞘形成。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。我们利用ChIP-ChIP阵列鉴定了与nuc- ErbB3相互作用的基因启动子，并聚集了雪旺细胞基因表达中的活性启动子。我们的长期目标是阐明nuc-ErbB3作为一种转录因子的功能，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。具体来说，我们的目标是：1。确定nuc-ErbB3在轴突-胶质相互作用和髓鞘形成中的功能意义；揭示nuc-ErbB3作为影响雪旺细胞与轴突和3相互作用的转录调节因子的作用。鉴定雪旺细胞细胞核中nuc-ErbB3的蛋白结合伙伴，并确定它们如何调节nuc-ErbB3的功能。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核变体调节神经系统细胞过程的新概念。此外，探索nucc - erbb3的转录作用及其在轴突-胶质相互作用和髓鞘形成过程中的功能，将为基因表达失调和/或髓鞘形成改变引起的周围神经病变提供有用的信息。

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.