Genetic Analyses of Dendrite Morphogenesis in Caenorhabditis Elegans

秀丽隐杆线虫树突形态发生的遗传分析

• 批准号: 10736702
• 负责人: Hannes Erich Buelow
• 金额: $ 43.56万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736702
• 关键词: Actins; Afferent Neurons; Aging; Alleles; Animals; Axon; Behavior; Binding Proteins; Binding Sites; Biochemical; Biological Process; Bipolar Neuron; Caenorhabditis elegans; Cell Adhesion Molecules; Cell Death; Cell Surface Receptors; Cell physiology; Cells; Complex; Cytoskeleton; Defect; Dendrites; Development; E2F transcription factors; Enhancers; Ensure; Environment; Epidermis; Genes; Genetic; Genetic Screening; Guanosine Triphosphate Phosphohydrolases; Image; Learning; Link; Maps; Mediating; Mental Retardation; Microtubules; Mitogen-Activated Protein Kinases; Modality; Molecular; Morphogenesis; Mutation; Nematoda; Neurodevelopmental Disorder; Neurons; Organism; Output; Pathway interactions; Pattern; Phenotype; Posture; Process; Proprotein Convertases; Research; Sampling; Sensory; Shapes; Signal Transduction; Skin; Stimulus; Structure; Suppressor Mutations; Surface; Synapses; Trees; Work; autism spectrum disorder; axon guidance; design; genetic analysis; genetic approach; genetic regulatory protein; human disease; insight; loss of function; model organism; mutant; neural circuit; neurodevelopment; neuropathology; neuropsychiatric disorder; novel; postmitotic; programs; receptive field; sensory input; somatosensory; transcription factor; transmission process

PI: Buelow, Hannes E. Project Summary Behavior in multicellular organisms is controlled by neural circuits in which neurons integrate synaptic input and compute output. Most neurons are bipolar and comprise dendrites and axons, which mediate reception and transmission of information, respectively. Dendrite branching is necessary for correct circuit assembly. We are using the pair of PVD and FLP neurons in the small nematode C. elegans to investigate basic genetic and molecular mechanisms of dendrite development. Both PVD and FLP neurons elaborate highly branched, non-overlapping dendritic arbors that employ conserved mechanisms during dendrite morphogenesis. Previously, we have focused our studies on genes that are required for the formation of the dendritic arbors of PVD and FLP neurons, with a focus on non-autonomously acting factors. In this proposal, we will focus on two aspects that have been previously understudied, both with regard to PVD development, but also in general with regard to dendrite patterning. In genetic screens we have identified several loci that restrict branching. In Specific Aim 1, we will study loci we identified in genetic modifier screens of a hypomorphic allele of the KPC-1/Furin proprotein convertase. We had previously found that KPC- 1/Furin functions cell-autonomously in PVD neurons to negatively regulate dendritic branching. This aim is designed to elucidate the molecular mechanisms by which KPC-1/Furin restricts branching. In addition, we will study an allele that constitutes a mutation in a transcription factor binding site of a gene encoding an actin regulatory protein. In Specific Aim 2, we will focus on a putative rab-related GTPase, which we have found to function in the epidermis to restrict dendrite branching. This aim is focused on determining the mechanisms by which this putative GTPase controls branching non- autonomously from the skin. In addition, we will study an allele that displays the same phenotype as a mutant in the GTPase to gain additional insight into the process of how branching is restricted. Finally, The FLP and PVD neurons provide a unique opportunity to study the processes of heterotypic tiling (i.e. the tiling of receptive fields between two different types of neurons) and the control of dendritic field size in molecular detail. In a combination of forward and candidate genetic screens we have identified a number of genes that regulate tiling between FLP and PVD dendrites. Therefore, in Specific Aim 3, we will determine the genetic and molecular mechanisms that govern heterotypic tiling and the control of field size. In summary, this proposal is aimed at understanding the molecular and genetic mechanisms that restrict and control dendritic branching on the one hand and, the processes that ensure establishment of non-overlapping dendritic fields of defined size between different types of neurons.

PI：Buelow，Hannes E. 项目概要 多细胞生物的行为由神经元整合的神经回路控制 突触输入和计算输出。大多数神经元是双极的，由树突和轴突组成， 分别介导信息的接收和传输。树突分支是 正确的电路组装所必需的。我们在小神经元中使用一对 P​​VD ​​和 FLP 神经元 线虫秀丽隐杆线虫研究树突的基本遗传和分子机制 发展。 PVD 和 FLP 神经元均形成高度分支、非重叠的树突 在树突形态发生过程中采用保守机制的乔木。此前，我们有 我们的研究重点是形成 PVD ​​树突状乔木所需的基因， FLP 神经元，重点关注非自主作用因素。在这个提案中，我们将重点关注两个 以前未充分研究的方面，既涉及 PVD ​​开发，也涉及 关于树突图案的一般性。在遗传筛选中，我们已经确定了几个位点 限制分支。在具体目标 1 中，我们将研究在基因修饰筛选中确定的基因座 KPC-1/弗林蛋白酶原蛋白转化酶的亚等位基因。我们之前发现 KPC- 1/Furin 在 PVD ​​神经元中发挥细胞自主功能，负向调节树突分支。这 目的旨在阐明 KPC-1/Furin 限制分支的分子机制。在 此外，我们将研究构成转录因子结合位点突变的等位基因 编码肌动蛋白调节蛋白的基因。在具体目标 2 中，我们将重点关注假定的与 rab 相关的 GTPase，我们发现它在表皮中发挥作用，限制树突分支。这个目标是 重点是确定这种假定的 GTPase 控制分支非-的机制。 自主地脱离皮肤。此外，我们将研究与 GTPase 中的突变体，以进一步了解如何限制分支的过程。 最后，FLP 和 PVD ​​神经元提供了研究异型过程的独特机会。 平铺（即两种不同类型神经元之间感受野的平铺）和控制 分子细节中的树突域大小。通过结合正向和候选遗传筛选，我们 已经确定了许多调节 FLP 和 PVD ​​树突之间平铺的基因。因此，在 具体目标 3，我们将确定控制异型平铺的遗传和分子机制 以及场大小的控制。总之，该提案旨在了解分子和 一方面限制和控制树突分支的遗传机制，另一方面限制和控制树突分支的过程 确保在不同类型之间建立定义大小的不重叠的树突域 神经元。