Early events in cortical development

描述(申请人提供)：新皮质，最大和最复杂的大脑结构，是哺乳动物独有的。它负责感觉和认知，以及对我们运动系统的控制。在其切向维度上，新皮质被组织成称为“区域”的多个区域，这些区域因其细胞结构和化学结构、丘脑皮质轴突(TCA)输入、第5层和第6层输出连接以及基因表达模式的主要差异而相互区别。这些特征形成了每个区域独特的特性的特定组合，并与基因表达的独特组合一起，决定了表征和区分成人区域的功能特化。第一个被证明可能影响区域化的转录因子是十年前才被发现的。尽管重要性毋庸置疑，但控制新皮质区域化的机制仍然粗略和有争议，主要局限于初级区域大小和位置的广泛轴向变化。在这里，我们提出了一系列旨在解决特定假设的特定假说，这些假说要求特定的调控基因来指定产生它们的祖细胞中皮质区域的身份和属性。这些研究将开辟新的天地，产生新的见解，并修正和纠正误解。这些研究包括确定特定的机制和转录因子，这些机制和转录因子需要指定主要的视觉区域、V1、其功能的冗余，以及它们在大脑皮层半球的活动限制。我们还将首次讨论高阶区域规范所涉及的遗传机制，并测试关于这些机制的具体假设。我们将重新评估Pax6 IS区域化的作用，并将其作为一个模型来研究区域视野大小的指定对皮质区域内感觉外围表征的影响，以及转录因子分级表达对其在建立感觉图谱和表征中功能的重要性。最后，我们将研究皮质固有的遗传变化对将感觉输入传递到皮质的主要感觉丘脑核团上区域图案的影响，并确定反向可塑性的机制，该机制用于系统地将丘脑核团与其目标区域匹配，并通过与其目标区域的逆行相互作用来重新形成它们的图案。这些研究将在小鼠身上使用条件功能丧失和功能获得遗传学进行，使用我们为这一提议制作的许多小鼠品系，并将利用为更高阶区开发的新基因标记。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，这将对新皮质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.