Developmental regulation by nuclear pore complex proteins

 描述（由申请人提供）：人类疾病的广泛潜在原因是基因表达的不正确空间或时间控制。核孔复合物（NPC），这是长期以来被认为是简单地作为一个网关，通过它分子进出细胞核，已成为一个重要的表达调节剂。在果蝇中发现了NPC和发育信号通路之间的一种新联系，这是基因转录的另一个关键调节因子，这激发了拟议的研究。Megator是Tpr核孔蛋白的果蝇同源物，被鉴定为Wg/Wnt抑制剂Tum的结合伴侣。在发育中的苍蝇翅膀中Megator功能的丧失破坏了Wg靶基因的表达，而不破坏Wg本身的产生，表明Megator是对Wg/Wnt信号传导的适当应答所必需的。随后发现的另外两种核孔蛋白（Nups）似乎也调节发育途径。Nup 154/155或Nup 214功能的丧失会严重破坏发育中的翅膀和腿，而不会影响其他发育中的组织。由Megator、Nup 154/155或Nup 214破坏引起的独特图案缺陷表明，它们参与了NPC结构完整性以外的细胞过程。它们可以靶向关键信号通路组分的核输入，独立于NPC调节信号通路，或以差异影响特定信号通路的靶基因的方式在核内组织染色质。该项目的目标是区分这些假设的组织特异性的Nup活动，使用强大的分子和遗传工具，可在果蝇模型系统。细胞间信号传导是所有动物胚胎发育所必需的。在人类中，丢失适当的信号会导致出生缺陷，而一些发育途径的过度活跃与各种儿童和成人癌症有关。由于果蝇的信号通路与人类高度保守，因此在果蝇中学到的知识将直接适用于人类细胞生物学。通过研究这些通路及其与NPC的相互作用，该项目旨在为不同的人类疾病状态提供新的见解，并可能揭示它们具有相似的细胞基础。在这些探索性实验中获得的结果将指导未来的研究信号转导和NPC之间的关系。这项工作有可能在理解核结构如何影响正常发育和疾病过程方面开辟新的道路。

 DESCRIPTION (provided by applicant): A broad underlying cause of human disease is the incorrect spatial or temporal control of gene expression. The nuclear pore complex (NPC), which was long regarded simply as a gateway through which molecules move in and out of the nucleus, has emerged as an important modulator of expression. A novel link between the NPC and developmental signaling pathways, another key regulator of gene transcription, has been discovered in Drosophila, which motivates the proposed research. Megator, the fly homolog of the Tpr nuclear pore protein, was identified as a binding partner for the Wg/Wnt inhibitor, Tum. Loss of Megator function in the developing fly wing disrupted expression of Wg target genes without disrupting production of Wg itself, indicating that Megator is required for proper response to Wg/Wnt signaling. Two other nucleoporins (Nups) that were identified subsequently also appear to regulate developmental pathways. Loss of Nup154/155 or Nup214 function drastically disrupted the developing wing and leg without affecting other developing tissues. The unique pattern defects caused by Megator, Nup 154/155 or Nup214 disruption suggest that they are involved in cellular processes beyond just structural integrity of the NPC. They may target the nuclear import of key signaling pathway components, modulate signaling pathways independently of the NPC, or organize chromatin within the nucleus in ways that differentially influence the target genes of specific signaling pathways. The goal of this project is to distinguish among these hypotheses for the tissue-specific nature of the Nup activities, using the powerful molecular and genetic tools available in the Drosophila model system. Cell to cell signaling is required for embryonic patterning in all animals. In humans, loss of proper signaling leads to birth defects, whereas hyperactivity of some developmental pathways is associated with a variety of childhood and adult cancers. Because signaling pathways in Drosophila are highly conserved with humans, what is learned in the fly will be directly applicable to human cell biology. By studying these pathways and their interaction with the NPC, this project aims to provide new insight into disparate human disease states, and may reveal that they share similar cellular underpinnings. The results obtained in these exploratory experiments will guide future investigation into the relationship between signal transduction and the NPC. This work has the potential to blaze a new trail in understanding how nuclear architecture influences normal development and disease processes.