Regulation of R7 axon tiling in the Drosophila visual system

果蝇视觉系统中 R7 轴突平铺的调节

• 批准号: 7699153
• 负责人: TORY G HERMAN
• 金额: $ 34.08万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7699153
• 关键词: Activins; Acute; Acute Brain Injuries; Adult; Axon; Brain; Caenorhabditis elegans; Cancer Etiology; Cells; Cessation of life; Clinical; Defect; Development; Disease; Down-Regulation; Drosophila genus; Family; Genes; Growth Cones; Health; Human; Injury; Invaded; Libraries; Mediating; Molecular Genetics; Mus; Mutation; Neoplasm Metastasis; Neuronal Differentiation; Neurons; Nuclear; Organism; Papio; Pathway interactions; Photoreceptors; Presynaptic Terminals; Process; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Specific qualifier value; Synapses; Testing; Time; Transcription Repressor/Corepressor; Visual system structure; Work; Wound Healing; axon growth; cell motility; member; neoplastic cell; novel; premature; prevent; protein expression; public health relevance; receptor; repaired; success; tool; transcription factor

DESCRIPTION (provided by applicant): TGF-??superfamily members have recently been shown to regulate axon pathfinding in a variety of organisms. However, the mechanisms by which TGF-?s influence axons are unclear. The TGF-??superfamily member Activin and its transcription factor effector dSmad2 are required to downregulate the motility of Drosophila R7 photoreceptor axons and thereby restrict them to non-overlapping targets. This proposal will take advantage of the powerful molecular and genetic tools available in Drosophila to determine how the Activin pathway is regulated during axon targeting and how its activation controls axon motility and tiling. A better understanding of this process is of significant clinical importance, as the success of therapies aimed at replacing or repairing damaged neurons will depend on whether axons can be induced to seek and recognize their targets in an adult context. In addition, many of the molecules that control axon motility also regulate cell motility; their misregulation is associated with the invasiveness of metastatic tumor cells, the primary cause of cancer death. The transcriptional repressor Tramtrack69 (Ttk69) normally blocks neuronal differentiation and is therefore downregulated in R7 precursors by Phyllopod (Phyl) to allow them to become neurons. Howvever, Ttk69 is later expressed in R7s and, like the Activin pathway, is required to prevent R7 axons from invading adjacent targets. Ttk69 expression in R7s does not depend on the Activin pathway. Aim 1 will test the hypothesis that Ttk69 acts upstream of the Activin pathway to control R7 growth cone motility and that its late expression in R7s is caused by downregulation of Phyl. Aim 2 will molecularly characterize two new genes that prevent R7 axons from invading adjacent targets and will determine whether they are regulators or targets of Ttk69 or the Activin pathway. Aim 3 will take a novel, efficient approach to identifying additional genes that increase the invasiveness of R7 axons, block their invasiveness, or decrease repulsion among R7 axons, a second mechanism that contributes to preventing overlap. PUBLIC HEALTH RELEVANCE: A better understanding of how axons find their targets is of significant clinical importance, since the success of therapies aimed at replacing or repairing neurons damaged by disease or acute injury will depend on whether axons can be guided to the correct targets. In addition, many of the molecules that control axon motility also control cell motility; their misregulation is associated with the invasiveness of metastatic tumor cells, the primary cause of cancer death. Finally, the Activin signaling pathway that we propose to study is required for a wide variety of processes important for human health, including wound repair and survival of neurons after acute brain injury.

描述（由申请人提供）：最近已证明TGF-？？但是，TGF-影响轴突的机制尚不清楚。需要TGF - ？超家族成员激活蛋白及其转录因子效应DSMAD2必须下调果蝇R7光感受器轴突的运动性，从而将其限制在非重叠靶标。该建议将利用果蝇中可用的强大分子和遗传工具来确定在轴突靶向过程中如何调节激活素途径，以及其激活如何控制轴突的运动性和平铺。更好地理解这一过程具有重要的临床重要性，因为旨在替换或修复受损神经元的疗法的成功将取决于是否可以诱导轴突在成人背景下寻求和识别其目标。另外，许多控制轴突运动性的分子也调节细胞运动。它们的不利地位与转移性肿瘤细胞的侵入性有关，这是癌症死亡的主要原因。转录阻遏物TRAMTRACK69（TTK69）通常会阻止神经元分化，因此在R7前体中被Phyllopod（Phyl）下调，使其成为神经元。 Howvever，TTK69后来在R7中表达，并且像激活素途径一样，需要防止R7轴突入侵相邻目标。 R7中的TTK69表达不取决于激活素途径。 AIM 1将检验以下假设，即TTK69在控制R7生长锥运动的上游作用于激活素途径的上游，并且其在R7中的后期表达是由Phyl的下调引起的。 AIM 2将分子表征两个新的基因，以防止R7轴突入侵相邻靶标，并确定它们是TTK69的调节剂还是TTK69或激活素途径的靶标。 AIM 3将采用一种新颖，有效的方法来识别增加R7轴突侵入性，阻止其侵入性，阻止其侵入性或减少R7轴突中的抑制作用的基因，这是一种有助于防止重叠的第二种机制。公共卫生相关性：更好地了解轴突如何找到其靶标具有重要的临床重要性，因为旨在替代或修复疾病或急性损伤神经元的疗法成功取决于是否可以将轴突引导到正确的靶标。另外，许多控制轴突运动的分子也控制细胞运动。它们的不利地位与转移性肿瘤细胞的侵入性有关，这是癌症死亡的主要原因。最后，我们建议研究的激活素信号传导途径对于对人类健康很重要的多种过程需要，包括急性脑损伤后的伤口修复和神经元的存活。