Left-Right Asymmetry of the Developing Diencephalon

发育中的间脑左右不对称

基本信息

批准号：
7844170
负责人：
MARNIE E HALPERN
金额：
$ 3.73万
依托单位：
CARNEGIE INSTITUTION OF WASHINGTON, D.C.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2010-10-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7844170
关键词：
Affect Axon Behavior Behavioral Biological Models Brain Brain Part Brain Stem Brain region Cell Nucleus Cells Cerebral Dominance Cognitive Complex Cues Development Dorsal Drosophila genus Exhibits Fiber Future Gene Expression Genes Genetic Genetic Markers Genetic Models Genetic Screening Goals Habenula Habenular Nucleus Handedness Homologous Gene Knowledge Label Left Link Maps Medial Mediating Membrane Methods Midbrain structure Modeling Mutagenesis Mutation Nature Neural Conduction Neural tube Neurodevelopmental Disorder Neurologic Neuropil Pathway interactions Pattern Prosencephalon Proteins Reporter Resources Right cerebral hemisphere Role Schizophrenia Screening procedure Side Signal Transduction Structure System Testing Tracer Transgenic Organisms Vertebrates Zebrafish axon guidance basal forebrain base density developmental neurobiology diencephalon insight interpeduncular nucleus molecular asymmetry molecular marker mutant nervous system disorder postsynaptic precursor cell presynaptic public health relevance research study tool

项目摘要

DESCRIPTION (provided by applicant): How left and right brain hemispheres acquire neuroanatomical and cognitive specializations remains a mystery. The zebrafish is a powerful genetic model to explore the developmental basis of laterality in the vertebrate brain. The larval dorsal diencephalon consists of an asymmetric pineal complex and adjacent paired nuclei, the medial habenulae (Ha), which exhibit left-right differences in size, organization, neuropil density, and patterns of gene expression. In all vertebrates, axons from the medial habenulae project within a prominent fiber bundle to a shared midbrain target, the interpeduncular nucleus (IPN), serving as an important relay between the basal forebrain and brainstem nuclei. In zebrafish, habenular projections from the left and right sides of the brain innervate the target differently, in part due to a molecular asymmetry in an axon guidance cue. Analysis of the zebrafish Ha-IPN conduction system has led to a model whereby a slight anatomical asymmetry in one part of the brain, the pineal complex, can influence an adjacent region and its connections, triggering a cascade of differences throughout the brain. This model has implications for the study of many developmental neurological disorders, including schizophrenia, which had been previously linked to abnormalities in brain laterality. The overall goal of the proposed study is to characterize the zebrafish Ha-IPN system in greater detail using a unique set of asymmetrically expressed and region specific molecular markers. Subnuclear regions of the habenular nuclei will be carefully defined and new transgenic tools applied to trace their distinct afferent and efferent projections. A mutation recently identified as mapping to the zebrafish wntless gene, that affects development of the Ha-IPN system, will be analyzed to test the hypotheses that Wnt signaling influences the proliferation of habenular precursor cells and the establishment of brain asymmetry. An ongoing mutagenesis screen will identify new mutations that perturb the development and asymmetry of the dorsal diencephalon, or are essential for the formation of Ha-IPN connectivity. These fundamental studies in a vertebrate genetic model will provide much needed insight into poorly understand yet evolutionarily conserved brain regions, which mediate diverse behaviors and have been implicated in neurodevelopmental disorders. PUBLIC HEALTH RELEVANCE: Specialization of the left and right hemispheres is essential for normal brain function and abnormalities in brain laterality have been linked to a number of developmental neurological conditions, including schizophrenia. The proposed experiments using a genetic model system, the zebrafish, will increase our knowledge of how left-right differences arise in the developing brain by characterizing asymmetry in a highly conserved yet poorly understood forebrain to midbrain neural conduction pathway.

描述（由申请人提供）：左脑半球和右脑半球如何获得神经解剖学和认知专业化仍然是一个谜。斑马鱼是探索脊椎动物大脑偏侧性发育基础的强大遗传模型。幼虫背侧间脑由不对称的松果体复合体和相邻的成对核、内侧缰核 (Ha) 组成，其在大小、组织、神经纤维密度和基因表达模式方面表现出左右差异。在所有脊椎动物中，来自内侧缰核的轴突在突出的纤维束内投射到共享的中脑目标，脚间核（IPN），作为基底前脑和脑干核之间的重要中继。在斑马鱼中，来自大脑左侧和右侧的缰核投射以不同的方式支配目标，部分原因是轴突引导线索中的分子不对称性。对斑马鱼 Ha-IPN 传导系统的分析得出了一个模型，通过该模型，大脑的一个部分（松果体复合体）的轻微解剖不对称可以影响邻近区域及其连接，从而引发整个大脑的一系列差异。该模型对许多发育性神经系统疾病的研究具有重要意义，包括精神分裂症，此前人们认为精神分裂症与大脑偏侧性异常有关。本研究的总体目标是使用一组独特的不对称表达和区域特异性分子标记更详细地表征斑马鱼 Ha-IPN 系统。缰核的亚核区域将被仔细定义，并应用新的转基因工具来追踪其独特的传入和传出投射。最近确定的斑马鱼 wntless 基因突变会影响 Ha-IPN 系统的发育，我们将对其进行分析，以测试 Wnt 信号传导影响缰核前体细胞增殖和大脑不对称性建立的假设。正在进行的诱变筛选将识别新的突变，这些突变会扰乱背侧间脑的发育和不对称性，或者对于 Ha-IPN 连接的形成至关重要。这些脊椎动物遗传模型的基础研究将为人们了解知之甚少但进化上保守的大脑区域提供急需的见解，这些区域介导多种行为并与神经发育障碍有关。公共卫生相关性：左右半球的特化对于正常的大脑功能至关重要，而大脑偏侧性异常与许多发育性神经系统疾病有关，包括精神分裂症。所提出的使用斑马鱼遗传模型系统的实验将通过表征高度保守但知之甚少的前脑到中脑神经传导通路的不对称性来增加我们对发育中大脑如何产生左右差异的了解。