Contributions of the striatal direct pathway to the formation of corticofugal axon trajectories

项目摘要/摘要： 纹状体环路异常与常见神经发育疾病的发病机制有关，包括 自闭症谱系障碍、抽动障碍、注意力缺陷/多动障碍和强迫症 无序。这些障碍的特点是运动、认知和社交障碍，通常会干扰 个人参与日常生活活动的能力。尽管有人认为基底节的缺陷 连通性可以驱动这些行为障碍，正常和正常的 病理神经回路仍然知之甚少，从而限制了治疗学的合理发展。 SOX8是一种转录因子，其缺失会导致纹状体直接通路突起受损。SOX8突变小鼠 似乎在皮质球和皮质脊髓投射方面也有缺陷，尽管该基因没有表达 在这些皮质神经元中。鉴于这两条轴突路径在内囊内非常接近地形成 在早期发育中，Sox8突变体中存在的解剖缺陷因此暗示了Sox8突变体在 引导皮质下行投射的直接通路。这个应用程序的中心假设 直接径路轴突是形成内囊和引导皮质球下行的先导 以及通过间脑和中脑的皮质脊髓轴突。 为了验证这一假设，Sox8 KO小鼠将被用作1)询问以下发育需求的工具 引导皮质神经下行轴突适当生长的直接途径和2)阐明 指导他们的机制(S)。利用Sox8-EGFP(直接途径)和Fezf2-Td番茄 (皮质逃逸途径)BAC转基因记者在整个发育过程中追踪这些途径，Aim 1将 专注于定义它们的发展轨迹，并确定它们之间的相互依存关系 正确的队形。在Aim 2中提议的实验将集中于建立体外检测以确定 直接和分离皮质激素途径的分子调节器，轴突颤动和突起。这些化验结果将是 用来评估一个候选因子Tenm2，用于调节观察到的Sox8突变体中明显的轴突缺陷。 本申请中概述的目标的成功完成将增加我们对纹状体如何 缺陷可影响其他主要轴索束的适当形成，从而导致 神经发育障碍

Project Summary/Abstract: Abnormal striatal circuitry is implicated in the pathogenesis of common neurodevelopmental conditions including autism spectrum disorder, tic disorder, attention-deficit/hyperactivity disorder, and obsessive-compulsive disorder. The motor, cognitive, and social impairments characteristic of these disorders often interfere with an individual’s ability to participate in activities of daily living. Despite the notion that defects in basal ganglia connectivity can drive these behavioral impairments, the genetic and molecular origins of both normal and pathologic neural circuits remain poorly understood, thereby limiting the rational development of therapeutics. Sox8 is a transcription factor whose loss results in impaired striatal direct pathway outgrowth. Sox8 mutant mice also appear to have defects in corticobulbar and corticospinal projections, despite that this gene is not expressed in these cortical neurons. Given that these two axon pathways form in close proximity within the internal capsule during early development, the anatomical defects present in Sox8 mutants thus suggest a novel role for the direct pathway in the guidance of descending cortical projections. The central hypothesis for this application is that direct pathway axons pioneer the forming internal capsule and guide descending corticobulbar and corticospinal axons through the diencephalon and midbrain. To test this hypothesis, Sox8 KO mice will be used as a tool to 1) interrogate the developmental requirement for the direct pathway in guiding the appropriate outgrowth of descending corticofugal axons and 2) elucidate the mechanism(s) by which it serves to guide them. Utilizing Sox8-EGFP (direct pathway) and Fezf2-TdTomato (corticofugal pathway) BAC transgenic reporters to trace these pathways throughout development, Aim 1 will focus on defining their developmental trajectories and determining their interdependence on one another for their proper formation. The proposed experiments in Aim 2 will focus on establishing in vitro assays to identify molecular regulators of direct and corticofugal pathway axon fasciculation and outgrowth. These assays will be used to evaluate a candidate factor, Tenm2, in mediating the observed axon defects apparent in Sox8 mutants. The successful completion of the aims outlined in this application will increase our understanding of how striatal defects can impact the appropriate formation of other major axon tracts and thereby contribute to the etiology of neurodevelopmental disorders