Left-Right Asymmetry of the Developing Diencephalon

描述(申请人提供)：左脑和右脑如何获得神经解剖学和认知特化仍然是一个谜。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。幼虫的背侧间脑由不对称的松果体复合体和相邻的成对的内侧缰核(Ha)组成，内侧缰核在大小、组织、神经纤维密度和基因表达模式方面表现出左右不同。在所有脊椎动物中，轴突从内侧缰核投射到一个共同的中脑靶点，即脚间核(IPN)，在基底前脑和脑干核团之间起着重要的中继作用。在斑马鱼中，大脑左右两侧的缰核投射对目标的支配是不同的，部分原因是轴突引导信号中的分子不对称。对斑马鱼Ha-IPN传导系统的分析导致了一个模型，即大脑一部分松果体复合体的轻微解剖不对称，就会影响邻近区域及其连接，引发整个大脑的级联差异。这一模型对包括精神分裂症在内的许多发育性神经疾病的研究具有启示意义，精神分裂症以前被认为与大脑偏侧异常有关。这项拟议研究的总体目标是使用一组独特的不对称表达和区域特定的分子标记来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它们不同的传入和传出投射。最近被发现定位到斑马鱼wnless基因的一个突变，影响到Ha-IPN系统的发育，将被分析以检验Wnt信号影响缰核前体细胞增殖和脑不对称建立的假说。正在进行的突变筛选将识别干扰背侧间脑发育和不对称性的新突变，或对Ha-IPN连接的形成至关重要。这些在脊椎动物遗传模型中的基础研究将为了解缺乏了解但在进化上保守的大脑区域提供亟需的洞察力，这些区域调节不同的行为，并与神经发育障碍有关。

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.