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业化仍然是一个谜。斑马鱼是研究脊椎动物脑侧化发育基础的有力遗传模型。幼虫背侧间脑由一个不对称的松果体复合体和相邻的成对核，内侧缰（Ha），表现出左右差异的大小，组织，神经元密度，和基因表达模式。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靶点，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传导系统的分析导致了一个模型，其中大脑的一部分，松果体复合体中轻微的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级联差异。这一模型对许多发育性神经障碍的研究具有重要意义，包括精神分裂症，精神分裂症以前被认为与大脑侧化异常有关。拟议的研究的总体目标是更详细地描述斑马鱼Ha-IPN系统使用一组独特的不对称表达和区域特异性分子标记。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。最近确定为映射到斑马鱼wntless基因，影响Ha-IPN系统的发展的突变，将进行分析，以测试Wnt信号影响缰前体细胞的增殖和建立大脑不对称的假设。一个正在进行的诱变筛选将确定新的突变，扰乱发展和不对称的背间脑，或必不可少的形成Ha-IPN连接。这些在脊椎动物遗传模型中的基础研究将为人们提供对尚不清楚但在进化上保守的大脑区域的深入了解，这些大脑区域介导不同的行为，并与神经发育障碍有关。 公共卫生相关性：左右半球的专门化对于正常的脑功能是必不可少的，并且大脑偏侧性的异常与许多发育神经学病症（包括精神分裂症）有关。使用遗传模型系统斑马鱼进行的拟议实验将通过表征高度保守但知之甚少的前脑至中脑神经传导通路中的不对称性，增加我们对发育中大脑中左右差异如何产生的知识。

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.