Transcriptional Factors in Forebrain Patterning

描述（由申请人提供）：大脑皮层是哺乳动物大脑中最大和最复杂的组成部分，在人类中达到顶峰。新皮层是大脑皮层中最大的区域，被组织成功能独特的“区域”，这些“区域”由细胞结构、连通性和基因表达模式的差异区分开来。新皮质区域的形成受两种因素的相互作用控制，一种是新皮质固有的遗传调控，以皮质祖细胞表达的转录因子（tf）为特征，另一种是将感觉信息传递到皮质区域的丘脑皮质（TCA）输入等外在影响。适当的皮质区域模式是一个关键的发育事件，因为皮质区域构成了感觉知觉的基础，控制我们的运动，调解我们的思想和行为。虽然不可否认的重要性，但相对而言，人们对实现的遗传学知之甚少。目前的研究结果表明，从分泌形态因子的大脑皮层周围的模式中心开始，有一个调控层次，这反过来又在皮层祖细胞中建立了tf的分级表达，指定了它们的区域身份，以及它们的神经元后代。此奖助金的主要目标是确定控制实现的tf，并在指定区域身份时定义它们的角色。需要处理的主要问题包括：(1)定义控制额叶/运动区和尾叶/感觉区（C/S）模式的tf，以及这些tf之间的相互作用，以平衡皮层的喙部-尾叶区模式；(2)区分这些tf在皮层板区域特异性的内在遗传规范中的作用，以及TCA输入在控制区域特异性和区分区域的特化分化中的作用。令人惊讶的是，人类新皮层每个主要区域的大小在正常人群中相差两到三倍之多。在老鼠身上，主要区域的大小在个体之间也有很大差异。这些区域大小的变化会对行为产生巨大的影响。例如，胚胎发育期间的基因操作会导致成人主要区域大小的比例减小或增大，从而导致模态特异性行为的重大缺陷。这些发现表明脑区有一个最佳大小，并强调了在发育过程中建立适当的指定脑区特征的tf表达水平的重要性，因为它们的变化会导致脑区大小的成比例变化，因此这些早期发育事件可能对以后的生活行为产生显著影响，影响表现，并可能导致多种形式的认知功能障碍和神经障碍。因此，本提案的第三个主要目标是建立小鼠作为区域模式差异与TF表达变化相关的模型，并在验证这种关系后，将其作为定义这些TF在人类区域模式中的作用的基础。

DESCRIPTION (provided by applicant): The cerebral cortex is the largest and most complex component of the mammalian brain, reaching its pinnacle in humans. The neocortex is the largest region of the cerebral cortex and is organized into "areas" that are functionally unique subdivisions distinguished by differences in cytoarchitecture, connectivity, and patterned gene expression. The specification of neocortical areas is controlled by an interplay between genetic regulation intrinsic to the neocortex, characterized by transcription factors (TFs) expressed by cortical progenitors, and extrinsic influences such as thalamocortical (TCA) input that relays sensory information to cortical areas. Proper area patterning of the cortex is a critical developmental event, because cortical areas form the basis for sensory perception, the control of our movements, and mediate our thoughts and behaviors. Although of undeniable importance, relatively little is known about the genetics of arealization. Current findings indicate a regulatory hierarchy that begins with patterning centers at the perimeter of the cerebral cortex that secrete morphogens, which in turn establish the graded expression of TFs in cortical progenitors that specify their area identities as well as those of their neuronal progeny. The major goal of this grant is to determine the TFs that control arealization, and define their roles in specifying area identities. The major issues to be addressed include: (1) defining the TFs that control the patterning of frontal / motor areas, and caudal / sensory (C/S) areas, as well as the interactions between these TFs to balance the rostral-caudal area patterning of the cortex, and (2) to distinguish roles for these TFs in the intrinsic genetic specification of area-specific properties in the cortical plate versus roles for TCA input in controlling the differentiation of area-specific properties and specializations that distinguish areas. Surprisingly, the size of each primary area in human neocortex varies by as much as two- to three-fold within the normal population. In mice, the sizes of a primary area can also vary significantly between individuals. These variations in area size can have dramatic effects on behavior. For example, genetic manipulations during embryonic development that result in proportional decreases or increases in the sizes primary areas in adults result in significant deficiencies at modality-specific behaviors. These findings indicate that areas have an optimal size, and underscore the importance of establishing during development the appropriate expression levels of TFs that specify area identities, as changes in them can result in a proportional change in area size, and thereby these early developmental events can have a prominent influence on behavior later in life, affecting performance and likely underlying many forms of cognitive dysfunction and neurological disorders. Therefore, the third major goal of this proposal is to establish the mouse as a model for relating differences in area patterning to variations in TF expression, and after validating this relationship, to use it as a basis to define roles for these TFs in area patterning in humans. PUBLIC HEALTH RELEVANCE: The neocortex is the largest and most complex component of the mammalian brain, reaching a pinnacle in humans. This proposal addresses the genetic mechanisms that control the patterning of the neocortex intro areas-- anatomically and functionally distinct subdivisions responsible for sensory perception, voluntary movements, thinking and behaviors. The findings from the proposed aims will form a basis of understanding of cognitive dysfunction and neurological disorders.