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: 8311756
• 负责人: TORY G HERMAN
• 金额: $ 32.09万
• 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/8311756
• 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; 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）：TGF-β超家族成员最近已被证明可以调节多种生物体中的轴突寻路。然而，TGF-β影响轴突的机制尚不清楚。 TGF-β超家族成员Activin及其转录因子效应子dSmad2需要下调果蝇R7光感受器轴突的运动性，从而将它们限制在非重叠的目标上。该提案将利用果蝇中可用的强大分子和遗传工具来确定激活素通路在轴突靶向过程中如何受到调节以及其激活如何控制轴突运动和平铺。更好地理解这一过程具有重要的临床意义，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环境中寻找和识别其目标。此外，许多控制轴突运动的分子也调节细胞运动。它们的失调与转移性肿瘤细胞的侵袭性有关，转移性肿瘤细胞是癌症死亡的主要原因。转录抑制因子 Tramtrack69 (Ttk69) 通常会阻止神经元分化，因此在 R7 前体中被 Phyllopod (Phyl) 下调，从而使它们成为神经元。然而，Ttk69 随后在 R7 中表达，并且与激活素途径一样，是防止 R7 轴突侵入邻近靶标所必需的。 R7s 中的 Ttk69 表达不依赖于激活素途径。目标 1 将检验以下假设：Ttk69 在激活素通路上游发挥作用，控制 R7 生长锥运动，并且其在 R7 中的晚期表达是由 Phyl 下调引起的。目标 2 将对阻止 R7 轴突侵入邻近靶标的两个新基因进行分子表征，并将确定它们是否是 Ttk69 或 Activin 通路的调节因子或靶标。 Aim 3 将采用一种新颖、有效的方法来识别额外的基因，这些基因可以增加 R7 轴突的侵袭性、阻止其侵袭性或减少 R7 轴突之间的排斥力，这是有助于防止重叠的第二种机制。公共健康相关性：更好地了解轴突如何找到其目标具有重要的临床意义，因为旨在替换或修复因疾病或急性损伤而受损的神经元的疗法的成功将取决于轴突是否可以被引导到正确的目标。此外，许多控制轴突运动的分子也控制细胞运动。它们的失调与转移性肿瘤细胞的侵袭性有关，转移性肿瘤细胞是癌症死亡的主要原因。最后，我们建议研究的激活素信号通路是对人类健康重要的多种过程所必需的，包括伤口修复和急性脑损伤后神经元的存活。