Transcriptional Factors in Forebrain Patterning

描述(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。新皮质是大脑皮层最大的区域，并被组织成功能独特的区域，这些区域通过细胞结构、连接性和模式基因表达的差异来区分。新皮质区域的指定是由新皮质固有的遗传调控和外部影响(如丘脑皮质(TCA)将感觉信息传递到皮质区域)相互作用控制的。皮质的适当区域模式是一个关键的发育事件，因为皮质区域形成了感官感知的基础，控制了我们的运动，并调节了我们的思想和行为。尽管具有不可否认的重要性，但人们对区域化的遗传学知之甚少。目前的发现表明，一种调控体系始于大脑皮层周边分泌形态原的图案中心，这反过来又建立了皮质前体细胞中TF的分级表达，该表达指定了它们及其神经元后代的区域身份。这项拨款的主要目标是确定控制区域化的技术框架，并确定它们在指定区域身份方面的角色。要解决的主要问题包括：(1)定义控制额叶/运动区和尾部/感觉(C/S)区的功能因子，以及这些功能因子之间的相互作用，以平衡皮质的嘴-尾部区域的图案，以及(2)区分这些功能因子在皮质板区特有属性的内在遗传规范中的角色与三氯乙酸输入在控制区域特定属性和区分区域的特化的分化中的角色。令人惊讶的是，在正常人群中，人类大脑皮层每个主要区域的大小差异高达两到三倍。在老鼠身上，主要区域的大小在个体之间也可能有很大的差异。这些区域大小的变化可能会对行为产生巨大影响。例如，胚胎发育期间的基因操作导致成人主要区域的大小按比例减少或增加，从而导致特定形态行为的显著缺陷。这些发现表明，区域有一个最佳的大小，并强调了在发育过程中建立指定区域身份的合适的转录因子表达水平的重要性，因为它们的变化可以导致区域大小的比例变化，从而这些早期发育事件可以对以后的生活行为产生显著影响，影响表现，并可能导致许多形式的认知功能障碍和神经障碍。因此，这项建议的第三个主要目标是建立小鼠作为将区域图案的差异与TF表达的差异相关联的模型，并在验证这种关系之后，将其用作定义这些TF在人类区域图案中的角色的基础。 与公共卫生相关：新皮质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。这一建议解决了控制新皮质导入区模式的遗传机制--在解剖学和功能上负责感觉、自愿运动、思维和行为的不同细分。来自拟议的AIMS的发现将形成理解认知功能障碍和神经障碍的基础。

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.