Genetic mechanisms that regulate left/right asymmetric neuron size

调节左/右不对称神经元大小的遗传机制

• 批准号: 7773011
• 负责人: Oliver Hobert
• 金额: $ 7.59万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7773011
• 关键词: Address; Affect; Applications Grants; Area; Behavioral Assay; Bilateral; Biological Models; Brain region; Caenorhabditis elegans; Calcium; Candidate Disease Gene; Cell Size; Cues; Dose; Gene Expression; Genes; Genetic; Genetic Epistasis; Genome; Growth; Handedness; Human; Image; Lateral; Left; Light; Link; Measures; Mental disorders; Molecular; Nematoda; Nervous system structure; Neurons; Orthologous Gene; Pathway interactions; Pattern; Phylogeny; Positioning Attribute; Regulation; Regulation of Cell Size; Regulator Genes; Regulatory Pathway; Reporter; Research; Resolution; Sensory; Signal Transduction; Sum; Suppressor Genes; Synapses; System; Testing; Transgenes; Tumor Suppressor Genes; cell type; genetic analysis; improved; insulin signaling; mutant; neuronal cell body; programs; public health relevance; response

DESCRIPTION (provided by applicant): PROJECT SUMMARY "Genetic and functional analysis of left/right asymmetric neuron size" Nervous systems are generally bilaterally symmetric on a structural level but are strongly lateralized (left/right asymmetric) on a functional level. Molecular and morphological correlates of functional laterality are sparse and, therefore, functional lateralization is poorly understood. However, it has been noted that symmetrically positioned, bilateral groups of neurons in functionally lateralized brain regions differ in the size of their soma. The genetic mechanisms that program these left/right asymmetric soma size differences are unknown. In fact, it is generally not well understood how the soma size of neurons is controlled throughout the nervous system (which contains neurons that differ in size by several orders of magnitude). We propose here to utilize the nematode C.elegans to study how the size difference of two, otherwise bilaterally symmetric chemosensory neuron is genetically controlled. To identify genes, we visualize the size difference in the neuron pair in a large panel of different genetic mutant backgrounds, which affect previously known pathways that control cell size in other systems. We will examine where these presumptive size regulators are expressed and how their expression is regulated. We will test whether altering the size of the two neurons impacts on specific response parameters to sensory cues. In sum, we combine two exciting and actively pursued areas of research that have not been combined before - the study of left/right asymmetry in the nervous system and the study of size control, using a model system that is particularly amenable to study these problems. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE "Genetic and functional analysis of left/right asymmetric neuron size" This grant proposal sets out to begin an analysis of the genetic regulation and functional relevance of cell size differences in the nervous system, using the nematode C.elegans as a model system. Lateral differences in neuron cell size are conserved across phylogeny, can be observed in humans and are disrupted in psychiatric disorders, illustrating the overall importance of this study.

描述（由申请人提供）： 神经系统在结构水平上通常是双侧对称的，但在功能水平上是强烈偏侧的（左/右不对称）。功能偏侧化的分子和形态学相关性是稀疏的，因此，功能偏侧化是知之甚少。然而，已经注意到，在功能性偏侧化的脑区域中，对称定位的双侧神经元组的索马大小不同。这种左右不对称索马大小差异的遗传机制尚不清楚。事实上，人们通常还不太了解神经元的索马大小是如何在整个神经系统中控制的（神经系统中包含大小相差几个数量级的神经元）。在这里，我们建议利用线虫研究两个，否则两侧对称的化学感受神经元的大小差异是如何遗传控制的。为了识别基因，我们在一个大的不同遗传突变背景的面板中可视化神经元对的大小差异，这些背景影响了以前已知的控制其他系统中细胞大小的途径。我们将研究这些假定的大小调节器在哪里表达，以及它们的表达是如何调节的。我们将测试改变两个神经元的大小是否会影响对感觉线索的特定反应参数。总之，我们结合了联合收割机两个令人兴奋的和积极追求的研究领域，以前没有结合-左/右不对称的神经系统的研究和大小控制的研究，使用一个模型系统，特别是适合研究这些问题。 公共卫生相关性： 项目叙述“左右不对称神经元大小的遗传和功能分析”该拨款提案旨在开始分析神经系统中细胞大小差异的遗传调节和功能相关性，使用线虫C.elegans作为模型系统。神经元细胞大小的横向差异在整个发育过程中是保守的，可以在人类中观察到，在精神疾病中被破坏，说明了这项研究的整体重要性。