Multistep mechanisms of Wnt signaling in asymmetric habenular neural circuit establishment

神经细胞群通常在大脑两侧相似地建立。它们通过延伸连接大脑不同区域的轴突形成网络，并允许信息流动。这些过程的失败可能会对生物体造成毁灭性的后果。这些双侧结构在两个半球的解剖结构和连通性以及功能上经常不同。这些不对称特征是否以及如何联系起来并可能影响我们的日常生活和行为是神经科学中一个长期存在的问题。最近在斑马鱼（Danio rerio）中建立了一个这样的左右不对称网络，称为habenular神经网络，作为研究大脑功能侧化问题的模型系统。在小辫发育过程中，Wnt信号级联影响构成小辫的不同类型神经元的产生。初步数据表明，在此过程中，需要对Wnt信号进行精确的及时控制。如果这个时间被打乱，一个缰状神经元亚型就不会产生，缰状神经元就会左右对称。介导这种时间控制的分子可能是分泌的Wnt抑制因子1 (Wif1)，它在缰状前体细胞中特异性表达，就在缰状神经元被指定的时候。有趣的是，Wif1似乎也在其自身表达的调控反馈循环中起作用。我的目的是评估在神经发生和大脑不对称的建立过程中Wnt信号的时间控制的新机制。进一步的初步实验表明，Wnt信号也可能参与了随后的缰神经传出轴突寻路。这些轴突如何在大脑中找到它们的路径仍然是未知的，数据表明Wnt控制着到目前为止尚未揭示的引导因素。因此，我项目的第二个目标是确定Wnt信号在轴突引导中的作用，并揭示所涉及的因素。所获得的知识将进一步允许在神经元和轴突水平上对不对称的大脑引入明确的、非侵入性的细微改变。这反过来又将促进对成年动物网络操作的功能后果的研究。综上所述，斑马鱼保守的缰状神经递质系统已成为研究脊椎动物大脑中神经元多样性、轴突寻径和左右不对称功能产生的强大模型。初步数据表明，Wnt信号的时间调控在缰状神经元的分化和轴突寻路中起着至关重要的作用。对这一信号级联的操作不仅将揭示缰神经网络的发展，而且还将揭示病理生理综合征和各种行为的发生。因此，我的工作可能会在发育生物学和神经科学领域内外产生广泛的影响。

Neuronal populations are usually established similarly on both sides of the brain. They form networks by extending axons which connect different brain areas and allow for the flow of information. A failure in these processes can have devastating consequences for the organism. These bilateral structures frequently differ between the two hemispheres in their anatomy and connectivity as well as in their function. If and how these asymmetric features are linked and may influence our daily life and behavior is a long-standing question in Neuroscience. One such left-right asymmetric network, named habenular neural network, has recently been established in the zebrafish (Danio rerio) as model system for studying this question of functional lateralization of the brain. During habenular development, the Wnt signaling cascade influences the generation of the different types of neurons the habenulae are made of. Preliminary data suggest that in this process the Wnt signals need to be precisely controlled in time. If this timing is disrupted, one habenular neuron subtype is not generated and the habenulae develop left-right symmetric. The molecule mediating this temporal control may be the secreted Wnt inhibitory factor 1 (Wif1), which shows specific expression in habenular precursor cells just around the time the habenular neurons are specified. Intriguingly, Wif1 also appears to act in a regulatory feedback loop on its own expression. My aim is to assess this novel mechanism of temporal control of Wnt signaling during neurogenesis and the establishment of brain asymmetry. Further preliminary experiments suggest that Wnt signals may also be involved in the subsequent pathfinding of habenular efferent axons. How these axons find their way through the brain has remained unknown and the data suggest that Wnt is controlling so far not revealed guidance factors. Therefore, the second aim of my project is to determine the role of Wnt signaling in axon guidance and to uncover the factor(s) involved. The gained knowledge will further allow to introduce defined, non-invasive subtle alterations into the asymmetric brain on the neuronal and the axonal level. This in turn will facilitate the study of functional consequences of network manipulations in adult animals.Taken together, the conserved habenular neurotransmitter system of the zebrafish has emerged as a powerful model to investigate the generation of neuronal diversity, axonal pathfinding and left-right asymmetric function in the vertebrate brain. Preliminary data suggest that temporal control of Wnt signaling plays a crucial role in the differentiation and axonal pathfinding of habenular neurons. Manipulation of this signaling cascade will shed light not only on how the habenular network develops but also on the genesis of pathophysiological syndromes and various behaviors. Thus, my work is likely to have widespread impact in- and outside the fields of Developmental Biology and Neuroscience.