Brain Ventricle Development and Mental Health

描述(申请人提供)：这项建议旨在利用斑马鱼的遗传方法来研究初始脑室充气的机制。脑室是一个保守的空腔系统，其中含有正常大脑功能所需的脑脊液。脑室结构的异常可导致脑积水，并与包括自闭症和精神分裂症在内的许多精神健康疾病有关。脑室发育的分子机制还知之甚少。斑马鱼是这项研究的极佳模型，因为脑室在整个发育过程中都可见，而且有许多遗传、分子和胚胎学工具可用。SIVE实验室的研究表明，脑室的形成是一个多步骤的过程，至少涉及两个步骤：连接相关蛋白形成和维持上皮完整性，以及脑室初始充气液体，这需要编码Na K ATPase的SNK(atp1a1a.1)基因。这项提议将检验SNK蛋白通过局部作用在初始脑室充气中发挥作用的假设。组织移植和镶嵌分析将被用来询问有限的野生型Atp1a1a.1功能是否可以拯救SNK突变体。此外，这项提议将检验多个基因与SNK协同作用以指导初始脑室充气的假设。从化学筛选和插入突变筛选中分离到的五个突变株显示出推测的脑膨胀表型。这些将被测试与SNK蛋白的协同效应。这项分析将利用斑马鱼来确定脑室膨胀的潜在机制，这些机制是建立正常大脑结构所必需的，而正常的大脑结构可能会受到精神健康障碍的干扰。

DESCRIPTION (provided by applicant): This proposal is designed to study the mechanisms underlying initial brain ventricle inflation, using a genetic approach in zebrafish. The brain ventricles are a conserved system of cavities containing cerebrospinal fluid that are required for normal brain function. Abnormalities in brain ventricle structure can lead to hydrocephaly and are correlated with many mental health disorders including autism and schizophrenia. The molecular mechanisms underlying brain ventricle development are poorly understood. The zebrafish is an excellent model for this study, as the brain ventricles are visible throughout development, and many genetic, molecular, and embryological tools are available. Research in the Sive laboratory has demonstrated that brain ventricle formation is a multi-step process, involving at least two steps: formation and maintenance of epithelial integrity by junction-associated proteins, and initial inflation of the ventricles with fluid, which requires the snk (atp1a1a.1) gene encoding a Na K ATPase. This proposal will test the hypothesis that the Snk protein functions in initial brain ventricle inflation by acting locally. Tissue transplants and mosaic analysis will be used to ask whether limited wild-type Atp1a1a.1 function can rescue snk mutants. Additionally, this proposal will test the hypothesis that multiple genes synergize with Snk to direct initial brain ventricle inflation. Five mutants isolated from chemical screens and two from an insertion mutagenesis screen show a putative brain inflation phenotype. These will be tested for synergistic effects with the Snk protein. This analysis will exploit the zebrafish to determine the mechanisms underlying brain ventricle inflation and that are required to build normal brain structure, which may be perturbed in mental health disorders.