Transcriptional Control of Terminal Differentiation

描述(申请人提供)：细胞周期退出与 末端分化是细胞发育的关键阶段。 然而，人们对这些机制知之甚少。 神经元和其他类型细胞的生长停滞/分化界面。是这样的 机制很可能不仅在疾病的发生或发展中发挥重要作用 末端分化的建立，也在维持其 正常的不可逆性。因此，阐明在这种情况下运行的机制 关键的发展关头也可能是 了解多种癌症的病因和治疗方法。长期的 该提案的目标是确定与增长相关的事件 逮捕在机制上与特定的转录调控有关 终末分化启动过程中的基因及其转录因子 激活这些启动子本身受生长停滞信号的调控。 这项建议侧重于神经发生，在此期间，神经母细胞的停滞导致 对有丝分裂后神经元的“诞生”和终末的开始 差异化。这一事件是神经元存活和 最终形成神经系统的复杂连接，也很重要 在建立特定神经元亚型的身份方面。一个潜在的 假说是将生长停滞和分化联系起来的机制 神经元是特定于细胞谱系的。一个主要目标是描述基础的特征 对于这种神经元的特异性，特别是调节的性质 转录因子参与其中。这些研究将有助于揭示 在发育过程中和在成人中控制神经发生的机制 神经系统，在这方面与潜在的治疗方法有关 神经退行性疾病。此外，它们对于理解它们很重要 一般的肿瘤发生，包括神经系统肿瘤。

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.