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，并通过对这些过程受到不利影响的动物模型的分析而得到相当大的信息。在这项提案中，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的调控问题，在该突变系中，这两个发育过程都是有缺陷的。纯合子分离(DISC)突变体在大脑皮层的基底外侧显示切向迁移的皮质中间神经元的异常堆积。此外，丘脑皮质的连接被破坏，基底前脑内的丘脑皮质轴突脱叉，无法上升到其皮质靶区。这两种缺陷都可能归因于错误的描述或基底前脑内的其他模式缺陷。在这项提案中，我们将检查这些缺陷是通过细胞自主机制还是非细胞自主机制发生的。具体地说，我们将使用脑片的器官类型培养，在其中我们将移植来自突变或野生动物的表达GFP的细胞，并观察标记细胞的迁移模式。此外，通过使用合适的分子标记进行一系列组织学实验，我们将确定突变体基底前脑内的地域身份，并将其与野生型进行比较。最后，我们将使用亲脂染料或转基因标记表达来追踪丘脑皮质和皮质分离纤维的详细情况，目的是表征它们的寻路缺陷。这些纤维束引导受到影响的方式被识别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。这项建议利用R21拨款机制，目的是开发一系列数据，作为假设驱动的研究计划的基础。了解受影响的视盘小鼠表型改变的确切性质将使我们能够继续分析基本的、可能相互关联的分子途径，这些分子途径对于调节切向迁移和丘脑皮质连接至关重要。) 公共卫生相关性：癫痫等神经疾病可能是大脑皮层内神经元不正确分布和/或连接的结果。在发育过程中，Wdfy3调节皮质中间神经元的迁移和丘脑与大脑皮层的连接，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. )