Wdfy3, a novel regulator of neuronal migration and connectivity

描述（由申请人提供）：大脑皮层的神经元迁移和连接仍然是发育神经生物学中非常感兴趣的领域，并且通过对这些过程受到不利影响的动物模型的分析得到了相当多的信息。在这项建议中，我们将通过分析一种新的突变小鼠品系，其中两个发育过程是有缺陷的，以解决切线迁移和丘脑皮层寻路的调节。纯合子断开（光盘）突变体显示异常积累的切向迁移皮层中间神经元在基底外侧方面的大脑皮层。此外，丘脑皮质连接被破坏，基底前脑内的丘脑皮质轴突解束，无法上升到它们的皮质目标区域。这两种缺陷都可能归因于基底前脑内的错误指定或其他模式缺陷。在这个建议中，我们将检查这些缺陷是否通过细胞自主或非细胞自主机制发生。具体来说，我们将使用脑切片的器官型培养物，其中我们将移植来自突变或野生型动物的表达GFP的细胞，并观察标记细胞的迁移模式。此外，通过一系列的组织学实验，使用适当的分子标记，我们将确定领土内的突变体的基底前脑的身份，并将它们与野生型进行比较。最后，我们将使用亲脂染料或转基因标记表达跟踪丘脑皮质和离皮质纤维的非常详细的目的是表征其寻路缺陷。这些纤维束的引导方式的共同点可能会为观察到的缺陷的分子和细胞机制提供线索。 该提案利用R21赠款机制，旨在开发一系列数据，以供假设驱动的研究计划使用。了解受影响的椎间盘小鼠的表型改变的确切性质，将使我们能够继续分析必要的和可能相互关联的分子途径，这些分子途径对切线迁移和丘脑皮质连接的调节至关重要。) 公共卫生相关性：神经系统疾病，如癫痫，可能是大脑皮层内神经元分布和/或连接不正确的结果。在发育过程中，Wdfy 3调节皮质中间神经元的迁移和丘脑与大脑皮质的连接，使其成为可能的诊断或治疗靶点。)

DESCRIPTION (provided by applicant): Neuronal migration and connectivity of the cerebral cortex remain areas of great interest in developmental neurobiology and have been informed considerably through the analysis of animal models in which these processes are adversely affected. In this proposal, we will address the regulation of tangential migration and thalamocortical pathfinding through the analysis of a novel mutant mouse line in which both developmental processes are defective. Homozygous disconnected (disc) mutants display abnormal accumulations of tangentially migrating cortical interneurons at basolateral aspects of the cerebral cortex. In addition, thalamocortical connectivity is disrupted with thalamocortical axons defasciculating within the basal forebrain and being unable to ascend to their cortical target areas. Both defects maybe attributed to misspecification or other patterning defects within the basal forebrain. In this proposal, we will examine if these defects occur through cell-autonomous or non-cell autonomous mechanisms. Specifically, we will use organotypic cultures of brain slices in which we will transplant GFP-expressing cells from mutant or wild-type animals and observe the migration patterns of labeled cells. In addition, through a series of histological experiments using appropriate molecular markers, we will determine territorial identities within the basal forebrain of the mutant and compare them to the wild-type. Finally, we will use lypophilic dyes or transgenic marker expression to trace thalamocortical and corticofugal fibers in great detail with the aim to characterize their pathfinding defects. Identified commonalities in the way guidance of these fiber tracts is affected may provide clues as to the molecular and cellular mechanisms underlying the observed defects. This proposal utilizes the R21 grant mechanism with the aim to develop a body of data on which a hypothesis driven research program can be based. Understanding the exact nature of the phenotypic alterations characterizing affected disc mice will allow us to pursue the analysis of essential and possibly interconnected molecular pathways that are crucial for the regulation of tangential migration and thalamocortical connectivity. ) PUBLIC HEALTH RELEVANCE: Neurological disorders, like epilepsy can be the result of incorrect distribution and/or connectivity of neurons within the cerebral cortex. During development Wdfy3 regulates migration of cortical interneurons and the connections of the thalamus to the cerebral cortex making it a possible diagnostic or therapeutic target. )