Gene regulatory network controlling commitment to ear identity

描述（由申请人提供）：脊椎动物内部是负责听觉和平衡的感觉器官中最复杂的。然而在发育过程中，它由单层上皮（耳基板）形成。在耳朵的发育过程中，多能祖细胞的潜能逐渐受到限制。这个过程是由调控基因控制的，其时间和空间表达模式在一个精心策划的基因调控网络（GRN）中受到严格调控。我们和其他人已经建立了一个控制内耳祖细胞特化和决定的事件层次，并确定了一些相关的调控基因。基于这些信息，我们已经建立了一个初步的网络控制这些过程，并设计了一个分子筛选，以确定新的耳指定。我们已经定义了共同调节的基因组，反映了不同阶段的耳朵规格。我们现在将利用基因组序列信息、同时监测100多个基因表达变化的新技术以及新开发的生物信息学工具来建立和验证初步的GRN。具体而言，我们将：“鉴定对耳诱导信号有反应的新基因“建立耳特异性转录因子和信号传导组分之间的上位关系“分离和表征控制耳中转录因子表达的增强子并检查直接输入“使用新开发的算法预测每个共表达组中基因的共同上游调节子并在体内测试预测的调节子。这将揭示控制内耳祖细胞特化的基本GRN及其末端靶基因。在未来，这个GRN将作为研究蛋白质-蛋白质和蛋白质-DNA相互作用的基础，以建立一个完整的网络，对这一过程进行定量分析和数学建模，以及发现影响听力和平衡的人类疾病的新候选基因的平台。

DESCRIPTION (provided by applicant): The vertebrate inner is the most complex of the sense organs responsible for hearing and balance. Yet during development it forms from a simple epithelium, the otic placode. During development of the ear, multipotent progenitor cells become progressively restricted in their potential. This process is controlled by regulatory genes whose temporal and spatial expression patterns are tightly regulated in an orchestrated gene regulatory network (GRN). We and others have established a hierarchy of events controlling the specification and determination of inner ear progenitors and identified some of the regulatory genes involved. Based on this information, we have established a preliminary network controlling these processes and designed a molecular screen to identify novel otic specifiers. We have defined co-regulated groups of genes that reflect different stages of ear specification. We will now harness genome sequence information, new technology to monitor changes in the expression of more than 100 genes simultaneously and newly developed bioinformatics tools to build up and verify the preliminary GRN. Specifically we will: " identify new genes responsive to otic inducing signals " establish the epistatic relationships between ear specific transcription factors and signaling components " isolated and characterize enhancers controlling transcription factor expression in the ear and examine direct inputs " predict common upstream regulators for genes in each synexpression group using newly developed algorithms and test the predicted regulators in vivo. This will uncover the basic GRN controlling the specification of inner ear progenitors together with its terminal target genes. In the future, this GRN will serve as a basis for studying protein-protein and protein-DNA interactions to build up a complete network, for quantitative analysis and mathematical modeling of this process, as well as a platform to discover new candidate genes for human disease affecting hearing and balance.