Analysis Of Gene Expression Regulatory Networks Controlling CNS Development

控制中枢神经系统发育的基因表达调控网络分析

• 批准号: 8158176
• 负责人: WARD F ODENWALD
• 金额: $ 99.96万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8158176
• 关键词: Development; Gene Expression

The objective of this program is to identify and characterize transcription factor regulatory networks controlling cell-identity decisions in the developing central nervous system (CNS). During CNS development, stem cells undergo multiple rounds of asymmetric cell divisions, producing either neuronal or glial progenitor cells with each division. Underpinning the formation of stem cell lineages are integrated regulatory networks that establish distinct cellular identities and, ultimately, create unique neuronal/glial subtypes within their lineages. Although much is known about early developmental decision leading to the formation of neural stem cells, little is understood about subsequent cell fate decisions that generate the unique functional identities of neurons or glia. The identification and functional characterization of the molecules and pathways/circuits underlying these cell fate decisions remain a central goal of neurobiology. We have discovered that in the developing Drosophila CNS most, if not all, stem cells transition through a series of synchronized gene expression programs during their asymmetric divisions. These temporal windows of gene expression are marked by the sequential production of different transcription factors that in turn help establish unique neural cell types. Our studies have revealed that the temporal domains are part of a global CNS regulatory network that coordinates cell fate-determining events. Our studies have demonstrated that when cultured in isolation, Drosophila stem cells maintain the correct temporal shifts in transcription factor gene expression. This cellular independence provides evidence that once neural lineage development is initiated no additional signaling cues between stem cells or adjacent tissues are required to trigger this cascade of regulatory gene expression. Our work on the characterization of novel genes identified from a differential cDNA expression screen resulted in new insights into the regulatory genes controlling CNS development. In particular, analysis of the novel genes, Nerfin-1 and Nerfin-2, reveal that they belong to a highly conserved Zn-finger transcription factor gene subfamily with human and nematode cognates. Nerfin-1 is expressed in neural stem cells while Nerfin-2 is expressed in a subset of brain neurons. Functional analysis of nerfin-1 has revealed that its encoded protein is required for proper axon pathfinding in the CNS. Understanding neural cell-identity decisions will ultimately have significant implications for identifying and treating developmental defects. Given that many, if not most, of the genes employed to construct a functioning nervous system are highly conserved among metazoans, deciphering the regulatory logic of Drosophila CNS development will most certainly aid in our understanding of human development. Additional information and publications describing this work can be obtained at our web site (http://intra.ninds.nih.gov/investigators.asp).

该计划的目标是识别和表征控制发育中的中枢神经系统（CNS）中细胞身份决策的转录因子调控网络。在中枢神经系统发育过程中，干细胞经历多轮不对称细胞分裂，每次分裂产生神经元或神经胶质祖细胞。支撑干细胞谱系形成的是整合的调控网络，这些网络建立了不同的细胞身份，并最终在其谱系内创建了独特的神经元/神经胶质亚型。尽管人们对导致神经干细胞形成的早期发育决策了解甚多，但对产生神经元或神经胶质细胞独特功能特性的后续细胞命运决策却知之甚少。这些细胞命运决定背后的分子和通路/电路的识别和功能表征仍然是神经生物学的中心目标。我们发现，在发育中的果蝇中枢神经系统中，大多数（如果不是全部）干细胞在不对称分裂期间通过一系列同步基因表达程序进行转变。这些基因表达的时间窗口以不同转录因子的顺​​序产生为标志，这些转录因子反过来又有助于建立独特的神经细胞类型。我们的研究表明，时域是协调细胞命运决定事件的全球中枢神经系统调节网络的一部分。我们的研究表明，当单独培养时，果蝇干细胞维持转录因子基因表达的正确时间变化。这种细胞独立性提供了证据，表明一旦神经谱系发育开始，干细胞或邻近组织之间不需要额外的信号线索来触发这种级联调节基因表达。我们对从差异 cDNA 表达筛选中鉴定出的新基因进行表征的工作，为控制中枢神经系统发育的调控基因带来了新的见解。特别是，对新基因 Nerfin-1 和 Nerfin-2 的分析表明，它们属于高度保守的锌指转录因子基因亚家族，与人类和线虫同源。 Nerfin-1 在神经干细胞中表达，而 Nerfin-2 在脑神经元子集中表达。 nerfin-1 的功能分析表明，其编码的蛋白质是中枢神经系统中正确的轴突寻路所必需的。了解神经细胞身份决定最终将对识别和治疗发育缺陷产生重大影响。鉴于用于构建功能神经系统的许多（如果不是大多数）基因在后生动物中高度保守，破译果蝇中枢神经系统发育的调控逻辑肯定有助于我们了解人类发育。描述这项工作的更多信息和出版物可以在我们的网站 (http://intra.ninds.nih.gov/investigators.asp) 上获得。