Molecular and functional mechanisms underlying binocular vision

描述(申请人提供)：两只眼睛在中央视觉结构中的投影的精细对准是精确呈现视觉世界的基础。我们发现，跨膜蛋白Ten_m3是这一过程的关键调节因子。缺乏Ten_m3的小鼠在同侧投射相对于对侧投射的映射中表现出严重的异常，并在视觉行为方面明显缺陷，这些缺陷可以被急性单眼失活逆转。这表明，改变的眼与眼之间的相互作用会抑制视觉，并且在缺乏这些相互作用的情况下，上游皮质回路足够完整，可以调节视觉行为。这些小鼠不仅有机会了解双目失配的功能后果，还可以探索双目视觉本身的机制。我们将确定Ten_m3调节轴突引导的机制。显著的同侧错误定位预测，在Ten_m3缺失的小鼠中，V1的输入将发生改变。我们将使用解剖学和功能学技术来确定V1的同侧和对侧输入的分布。我们将测试这一有趣的预测，即功能性眼优势柱将在V1中形成，并评估视觉体验在其生成中的作用。数据表明，V1的同侧和对侧输入之间将存在功能错位。将使用电生理记录、内在信号成像和双光子成像来检查同侧和对侧输入的反应、感受场和地图，以及它们之间的相互作用。我们将探索改变的眼间相互作用导致夸大形式的眼间抑制的可能性，并且V1是这一效应的重要部位。根据它的表达模式，我们认为Ten_m3调节大脑皮层的区域化和连通性，并将确定它在这些过程中的作用。Ten_m3下游的细胞内信号转导途径尚不清楚。我们的数据显示，缺乏zic4的小鼠表现出与Ten_m3突变相反的表型。Ten_m3和zic4之间相互作用的性质将被确定，并确定该信号通路的新成分。这些发现将对理解异常的双眼视差如何导致斜视和弱视等视觉障碍的功能障碍，以及制定治疗策略具有重要意义。 与公共卫生的相关性：已证明TEN_M3有助于视觉系统的发展。视觉输入的不正确处理可能导致弱视、斜视或失明；此外，感觉处理缺陷与自闭症和其他认知和社会发展障碍有关。计划中的实验有望阐明Ten_m3表达影响双眼视觉发育的机制，从而为视觉功能障碍的治疗设计提供新的依据。

DESCRIPTION (provided by applicant): The exquisite alignment of projections from the two eyes in central visual structures is fundamental for a precise representation of the visual world. We have discovered that the transmembrane protein Ten_m3 is a critical regulator of this process. Mice that lack Ten_m3 show profound abnormalities in mapping of ipsilateral projections relative to contralateral projections, and marked deficits in visual behavior which are reversed by acute monocular inactivation. This indicates that altered interocular interactions act to suppress vision, and that the upstream cortical circuitry is sufficiently intact to mediate visual behavior in the absence of these interactions. These mice allow the opportunity to not only understand the functional consequences of a binocular mismatch, but to probe the mechanisms which underlie binocular vision itself. We will determine the mechanism by which Ten_m3 regulates axon guidance. The pronounced ipsilateral mistargeting predicts that inputs to V1 will be altered in Ten_m3 null mice. We will use anatomical and functional techniques to determine the distribution of ipsilateral and contralateral inputs to V1. We will test the intriguing prediction that functional ocular dominance columns will form in V1, and assess the role of visual experience in their generation. The data suggest there will be a functional misalignment between the ipsilateral and contralateral inputs to V1. The responses, receptive fields and maps of ipsilateral and contralateral inputs, and their interactions, will be examined using electrophysiological recording, intrinsic signal imaging, and two-photon imaging. We will explore the possibility that altered interocular interactions lead to an exaggerated form of interocular suppression and that V1 is an important locus of this effect. Based on its expression pattern, we propose that Ten_m3 regulates cortical arealization and connectivity and will determine its role in these processes. The intracellular signaling pathways which operate downstream of Ten_m3 are unknown. Our data shows that mice lacking zic4 display the inverse phenotype to Ten_m3 mutants. The nature of the interactions between Ten_m3 and zic4 will be determined and novel components of this signaling pathway identified. These findings will have important implications for understanding how abnormal binocular disparity leads to dysfunction in visual disorders such as strabismus and amblyopia, and for developing strategies for their treatment. PUBLIC HEALTH RELEVANCE: Ten_m3 has been shown to be instrumental in development of the visual system. Improper processing of visual inputs can result in amblyopia, strabismus, or blindness; in addition, deficits in sensory processing have been linked to autism and other disorders of cognitive and social development. The planned experiments promise to elucidate the mechanisms by which Ten_m3 expression affects the development of binocular vision, and thus to provide a novel basis for the design of therapies for visual dysfunction.