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通性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已经得到了相当大的了解。在本提案中，我们将通过分析一种新的突变小鼠系来解决切向迁移和丘脑皮质寻径的调节，该突变小鼠系的两个发育过程都有缺陷。纯合子断开（盘）突变体在大脑皮层的基底外侧显示切向迁移的皮层中间神经元的异常积累。此外，丘脑皮质连通性被破坏，丘脑皮质轴突在基底前脑内血液循环中断，无法上升到皮层目标区域。这两种缺陷都可能是由于基底前脑内的错误描述或其他模式缺陷。在本提案中，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，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，通过一系列使用适当分子标记的组织学实验，我们将确定突变体基底前脑内的领土身份，并将其与野生型进行比较。最后，我们将使用亲氧染料或转基因标记表达来详细追踪丘脑皮质和皮质纤维，目的是表征它们的寻路缺陷。在这些纤维束的引导方式中确定的共性可能为观察到的缺陷背后的分子和细胞机制提供线索。本提案利用R21资助机制，目的是开发一个假设驱动的研究项目可以基于的数据体。了解受影响的椎间盘小鼠表型改变的确切性质，将使我们能够继续分析对切向迁移和丘脑皮质连通性调节至关重要的基本和可能相互关联的分子途径。)

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. )