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。新皮层是大脑皮层的最大区域，并且被组织成功能独特的细分“区域”，其通过细胞结构、连接性和模式化基因表达的差异来区分。新皮层区域的规范是由新皮层内在的遗传调节和外在影响之间的相互作用控制的，所述遗传调节的特征在于由皮层祖细胞表达的转录因子（TF），所述外在影响例如将感觉信息传递到皮层区域的丘脑皮层（TCA）输入。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，并调解我们的思想和行为。尽管不可否认的重要性，但人们对现实化的遗传学知之甚少。目前的研究结果表明，一个监管的层次结构，开始与图案中心在周边的大脑皮层分泌形态，这反过来又建立了分级表达的TF皮质祖细胞，指定他们的区域身份，以及他们的神经元后代。这项补助金的主要目标是确定控制区域化的TF，并定义它们在指定区域身份方面的作用。需要处理的主要问题包括：（1）定义控制额叶/运动区和尾侧/感觉（C/S）区的图案化的TF，以及这些TF之间的相互作用以平衡皮质的头侧-尾侧区图案化，以及（2）区分这些TF在区域-皮质板中的特定属性与TCA输入在控制区分区域特定属性和区分区域的专业化的分化中的作用。令人惊讶的是，人类新皮层中每个主要区域的大小在正常人群中的变化高达两到三倍。在小鼠中，主要区域的大小也可以在个体之间显著变化。这些区域大小的变化会对行为产生巨大的影响。例如，在胚胎发育过程中的遗传操作导致成年人主要区域的大小成比例地减少或增加，从而导致模态特定行为的显著缺陷。这些发现表明，区域具有最佳大小，并强调了在发育期间建立指定区域身份的TF的适当表达水平的重要性，因为它们的变化可能导致区域大小的成比例变化，因此这些早期发育事件可能对以后的行为产生显著影响。影响表现并可能导致许多形式的认知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，用于将区域图案化差异与TF表达的变化相关联，并且在验证这种关系之后，将其用作定义这些TF在人类区域图案化中的作用的基础。 公共卫生相关性：新皮层是哺乳动物大脑中最大、最复杂的组成部分，在人类中达到顶峰。该提案涉及控制新皮层引入区模式的遗传机制-解剖学和功能上不同的细分负责感官知觉，自愿运动，思维和行为。从拟议的目标中得出的结果将成为理解认知功能障碍和神经系统疾病的基础。

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.