Early events in cortical development

描述（由申请人提供）：新皮层，最大和最复杂的大脑结构，是哺乳动物独有的。它负责感觉知觉和认知，以及控制我们的运动系统。在切向维度上，新皮层被组织成被称为“区域”的细分，这些细分通过细胞结构和化学结构、丘脑皮质轴突（TCA）输入和第5层和第6层输出连接以及基因表达模式的主要差异来区分彼此。这些属性形成了每个区域独特属性的特定组合，并与独特的基因表达组合一起，决定了表征和区分成人区域的功能专门化。首个显示可能影响实现的转录因子在十年前才被发现。虽然具有无可争辩的重要性，但控制新皮层实现的机制仍然是粗略的和有争议的，并且很大程度上局限于主要区域大小和位置的广义轴向变化。在这里，我们提出了一系列的目标，以解决某些调节基因的要求的具体假设，以指定产生它们的祖细胞皮质区域的身份和特性。这些研究将开辟新的领域，产生新的见解，并修正和纠正误解。这些研究包括确定指定主要视觉区域V1所需的特定机制和转录因子，它们的功能冗余以及它们在皮质半球上的作用限制。我们还将首次讨论涉及高阶区域规范的遗传机制，并对这些机制的具体假设进行测试。我们将重新评估Pax6的作用，并以其功能为模型，研究区域场大小的规格对皮层区域内感觉外围表征的影响，以及转录因子的分级表达在建立感觉地图和表征中的重要性。最后，我们将研究皮层内在遗传变化对将感觉输入传递给皮层的主要感觉丘脑核的区域模式的影响，并定义反向可塑性的机制，该机制有助于系统将丘脑核与其目标区域匹配，并通过与其目标区域的逆行相互作用重新设置它们。这些研究将在小鼠中使用条件丧失和功能获得遗传学，使用我们为本提案制作的许多小鼠系，并将利用为高阶区域开发的新基因标记。此外，我们提出的大量初步发现支持我们的假设，并表明我们的发现将导致新概念的发展，在某些情况下挑战和取代教条，这将对新皮层的发育和可塑性产生影响。

DESCRIPTION (provided by applicant): The neocortex, the largest and most complex brain structure, is unique to mammals. It is responsible for sensory perception and cognition, as well as control of our motor systems. In its tangential dimension, the neocortex is organized into subdivisions referred to as "areas" that are distinguished from one another by major differences in their cytoarchitecture and chemoarchitecture, thalamocortical axon (TCA) input and layer 5 and 6 output connections, and patterns of gene expression. These attributes form a specific combination of properties unique for each area, and together with unique combinations of gene expression, determine the functional specializations that characterize and distinguish areas in the adult. The first transcription factor shown to potentially influence arealization was only identified a decade ago. Although of inarguable importance, the mechanisms controlling arealization of the neocortex remain sketchy and controversial, and are largely limited to generalized axial changes in the size and position of primary areas. Here we propose a series of aims to address specific hypotheses on the requirements of certain regulatory genes to specify the identities and properties of cortical areas in the progenitors that generate them. These studies will break new ground, generate novel insights, and revise and correct misconceptions. The studies include determining the specific mechanisms and transcription factors that are required to specify the primary visual area, V1, redundancy in their function, and limits in their action across the cortical hemisphere. We will also address for the first time the genetic mechanisms involved in the specification of higher order areas and test specific hypotheses on these mechanisms. We will reassess roles for Pax6 is arealization, and use its function as a model for studying the effects of specification of area field size on the representation of the sensory periphery within a cortical area, and the importance of graded expression of transcription factors on their function in establishing sensory maps and representations. Finally, we will investigate the influence of cortex-intrinsic genetic changes to area patterning on the principal sensory thalamic nuclei that relay sensory input to cortex, and define mechanisms of reverse plasticity that serve to systems-match thalamic nuclei to their target areas, and to re-pattern them through a retrograde interaction with their target area. These studies will be carried out using conditional loss- and gain-of-function genetics in mice, using numerous mouse lines that we have made for this proposal, and will make use of new gene markers developed for higher order areas. Further, the considerable amount of preliminary findings that we present support our hypotheses, and indicate that our findings will lead to the development of new concepts, in some cases challenging and replacing dogma, that will have implications for neocortical development and plasticity.