Transcriptional Control of Terminal Differentiation

描述（由申请人提供）：细胞周期退出与 终末分化代表细胞发育的关键阶段。 然而，关于在大脑中运作的机制知之甚少。 在神经元和其他细胞类型中的生长停滞/分化界面。等 机制可能不仅在发病或 建立终端分化，而且在维护其 常态不可逆性因此，阐明在这种情况下运作的机制， 关键的发展关头也可能是重要的， 了解多种癌症的病因和治疗方法。长期 本提案的目标是确定与增长相关的事件 阻滞机制与特定的转录调控有关， 基因在终末分化开始时以及转录因子如何 激活这些启动子本身受生长停滞信号调节。 这项建议的重点是神经发生，在此期间，神经母细胞的逮捕导致 到有丝分裂后神经元的“诞生”和终末细胞的出现， 分化这一事件是神经元存活的主要决定因素， 最终形成神经系统的复杂线路， 来确定特定神经元亚型的身份。下面的 一种假说认为，生长停滞和分化之间的联系机制， 神经元是细胞谱系特异性的。一个主要目标是描述基础 对于这种神经元特异性，特别是调节的性质， 转录因子参与。这些研究将有助于揭示 在发育过程中以及在成人中控制神经发生的机制 神经系统，并在这方面与潜在的治疗有关， 神经退行性疾病此外，它们对于理解 肿瘤发生，包括神经系统的瘤形成。

DESCRIPTION (provided by applicant): The linkage between cell cycle exit and terminal differentiation represents a critical phase of cellular development. However, very little is known regarding the mechanisms functioning at the growth arrest/differentiation interface in neurons and other cell types. Such mechanisms are likely to play a vital role in not only the onset or establishment of terminal differentiation, but also in the maintenance of its normal irreversibility. Thus, elucidating the mechanisms operating at this critical developmental juncture is also likely to be importance in understanding the etiology and treatment of many forms of cancer. The long-term goal of this proposal is to determine how the events associated with growth arrest are mechanistically linked to transcriptional regulation of specific genes during onset of terminal differentiation and how transcription factors activating these promoters are themselves regulated by growth arrest signals. This proposal focuses on neurogenesis, during which arrest of neuroblasts leads to the "birth" of postmitotic neurons and the onset of terminal differentiation. This event is a major determinant of which neurons survive and ultimately form the complex wiring of the nervous system, and also is important in establishing the identities of specific neuronal sub-types. An underlying hypothesis is that the mechanisms linking growth arrest and differentiation in neurons are cell lineage-specific. A major goal is to characterize the basis for this neuron-specificity and, in particular, the nature of the regulatory transcription factors involved. These studies will help to reveal the mechanisms controlling neurogenesis during development as well as in the adult nervous system, and in this regard are relevant to potential therapies for neuro-degenerative diseases. Further, they are important for understanding tumorigenesis in general, including neoplasias of the nervous system.