Transcriptional Factors in Forebrain Patterning

摘要 大脑皮层是哺乳动物大脑中最大和最复杂的组成部分， 人类的巅峰新皮层是大脑皮层中最大的区域，被组织成“区域” 它们是功能上独特的亚类，以细胞结构、连接性和 模式化基因表达新皮层区域的特化是由以下因素之间的相互作用控制的： 新皮质固有的遗传调节，其特征在于由以下表达的转录因子（TF）： 皮质祖细胞，以及外部影响，如丘脑皮质（TCA）输入，中继感觉 信息传递到皮层区域。大脑皮层的适当区域模式是一个关键的发育事件，因为 皮层区域形成了感官知觉的基础，控制我们的运动，并调解我们的行为。 思想和行为。虽然不可否认的重要性，相对较少的是知道的遗传学， 区域化目前的研究结果表明，一个监管层次，开始与图案中心在 分泌形态发生素的大脑皮层周边，这反过来又建立了 皮质祖细胞中的转录因子，指定其区域身份以及其神经元后代的区域身份。的 该基金的主要目标是确定控制实现的TF，并定义它们在指定 地区身份。要解决的主要问题包括：（1）定义控制图案化的TF， 额叶/运动区和尾/感觉（C/S）区，以及这些TF之间的相互作用， 平衡皮质的喙尾区图案，以及（2）区分这些TF在大脑中的作用。 皮质板中区域特异性特性的内在遗传特异性与TCA输入的作用 控制区分区域的区域特定属性和专业化的差异。 令人惊讶的是，人类新皮层中每个主要区域的大小变化多达两到三倍 在正常人群中。在小鼠中，初级区域的大小也可以在 个体这些区域大小的变化会对行为产生巨大的影响。例如遗传 在胚胎发育过程中的操作，导致成比例的减少或增加的大小 成年人的主要区域导致特定于模态的行为的显著缺陷。这些发现 指出区域有一个最佳大小，并强调在开发过程中建立 指定区域身份的TF的适当表达水平，因为它们的变化可能导致 面积大小的比例变化，从而这些早期发育事件可以有一个突出的 对以后生活中的行为产生影响，影响表现，并可能成为许多形式认知的基础。 功能障碍和神经系统疾病。因此，本提案的第三个主要目标是建立 小鼠作为模型，用于将区域图案的差异与TF表达的变化相关联，以及 验证这种关系，将其作为基础来定义这些TF在人类区域模式中的作用。

Abstract 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.