Left-Right Asymmetry of the Developing Diencephalon

描述（由申请人提供）：左右脑半球如何获得神经解剖学和认知专门化仍然是一个谜。斑马鱼是一个强大的遗传模型来探索脊椎动物大脑侧性的发育基础。幼虫背间脑由一个不对称的松果体复合体和相邻的成对核——内侧habenulae （Ha）组成，它们在大小、组织、神经细胞密度和基因表达模式上表现出左右差异。在所有脊椎动物中，来自内侧束的轴突在一个突出的纤维束内投射到一个共同的中脑目标，即脚间核（IPN），作为基底前脑和脑干核之间的重要中继。在斑马鱼中，来自大脑左右两侧的缰状突起对目标的神经支配不同，部分原因是轴突引导线索的分子不对称。对斑马鱼Ha-IPN传导系统的分析得出了一个模型，即大脑中松果体复合体的轻微解剖不对称可以影响相邻区域及其连接，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疾病的研究具有启示意义，包括精神分裂症，这在以前被认为与脑侧性异常有关。提出的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。将仔细定义小核的亚核区域，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。最近发现的一个突变定位于斑马鱼的wntless基因，该基因影响Ha-IPN系统的发育，将进行分析，以验证Wnt信号影响habenular前体细胞的增殖和大脑不对称的建立的假设。正在进行的突变筛选将确定干扰背间脑发育和不对称性的新突变，或对Ha-IPN连接形成至关重要的突变。这些脊椎动物遗传模型的基础研究将为我们了解尚不清楚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。

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.