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).

该程序的目的是识别和表征转录因子调节网络，以控制发展中枢神经系统（CNS）中细胞认同的决策。在中枢神经系统发育过程中，干细胞会经历多轮不对称细胞分裂，每种分裂都会产生神经元或神经胶质祖细胞。基于干细胞谱系的形成的基础是集成的调节网络，它们建立了不同的细胞身份，并最终在其谱系中创建独特的神经元/神经胶质亚型。尽管对导致神经干细胞形成的早期发育决策知之甚少，但几乎没有什么理解的是随后产生神经元或神经胶质的独特功能身份的细胞命运决策。这些细胞命运决定的分子和途径/电路的鉴定和功能表征仍然是神经生物学的核心目标。我们发现，在发展中的果蝇中枢神经系统中，干细胞在不对称分裂过程中通过一系列同步基因表达程序过渡。这些基因表达的时间窗口以不同的转录因子的顺​​序产生为标志，这些因素又有助于建立独特的神经细胞类型。我们的研究表明，时间域是协调细胞命运确定事件的全球CNS调节网络的一部分。我们的研究表明，果蝇干细胞在分离培养时保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，一旦开始神经谱系的发展，干细胞或相邻组织之间就无需其他信号线索来触发这种调节基因表达的级联。我们在从差异cDNA表达筛选中鉴定出的新型基因表征的工作导致对控制中枢神经系统发育的调节基因的新见解。特别是，对新型基因Nerfin-1和nerfin-2的分析表明，它们属于具有人和线虫认识的高度保守的Zn指转录因子基因基因。 Nerfin-1在神经干细胞中表达，而Nerfin-2则在脑神经元的一部分中表达。 Nerfin-1的功能分析表明，其编码的蛋白需要在中枢神经系统中进行适当的轴突路径。了解神经细胞认同的决策最终将对识别和治疗发育缺陷产生重大影响。鉴于许多（即使不是大多数）用于构建功能性神经系统的基因在后生动物中是高度保守的，因此破译果蝇中枢神经系统发展的调节逻辑肯定会有助于我们对人类发展的理解。可以在我们的网站（http://intra.ninds.nih.gov/investigators.asp）上获得描述这项工作的其他信息和出版物。