Patterning of Drosphila Embryos by the Dorsal-dependent Gene Network

描述（由申请人提供）：基因表达的阈值输出对于所有后生动物的模式化都很重要。在后基因组时代，发育生物学领域的核心挑战之一是确定大量基因的差异表达以形成胚胎，以及这些基因随后如何控制特化组织的分化。研究发育的全基因组方法通常会产生许多被预测在调节生物学中起作用的基因列表。我们建议利用基因组数据来研究果蝇发育的转录调控，并将该系统中发现的机制与人类联系起来。具体来说，我们感兴趣的是如何背腹图案的果蝇胚胎是由背依赖形态梯度控制。通过微阵列分析，我们发现约50个基因的转录调控Dorsal和差异表达沿着背腹轴在不同的领域。几个已鉴定的基因编码的转录因子可能与Dorsal一起发挥作用，以控制基因表达的模式沿着背腹轴。我们对背侧依赖性靶基因表达的初步结果也提出了一些关于基因表达阈值输出的问题。特别是，背靶基因的表达是如何在空间上限制到不同的域沿着背腹轴和做转录因子，在微阵列筛选功能与背一起控制图案？我们为解决这些问题提出了两个具体目标：（1）通过增强子分析鉴定与Dorsal一起起作用的转录因子（使用我们已经鉴定的对表达重要的顺式调控基序），以及（2）表征我们提出的有助于胚胎图案化的两个假定的转录因子的功能。（Neu2，通过我们的微阵列研究鉴定，Wek，在遗传筛选中鉴定的母系表达基因）。表征这些转录因子用于影响不同结构域中差异基因表达的机制将为基因表达控制Dy形态发生梯度的调节提供普遍适用的见解。这些研究还可以提供对一般Rel转录因子的转录调控的见解，因此有可能对NF κ B调控的过程提供深远的影响，包括免疫反应，癌症和过敏性炎症。

DESCRIPTION (provided by applicant): Threshold outputs of gene expression are important for patterning all metazoa. One of the central challenges in the field of developmental biology in this post-genomics era is to determine how large numbers of genes are differentially expressed to pattern the embryo and how these genes subsequently control differentiation of specialized tissues. Whole-genome approaches to studying development typically generate many lists of genes that are predicted to function in regulating biology. We propose to utilize genomic data to study transcriptional regulation of development in Drosophila and relate the mechanisms uncovered in this system to humans. Specifically, we are interested in how dorsoventral patterning of the Drosophila embryo is controlled by the Dorsal-dependent morphogen gradient. By microarray analysis, we have found that ~50 genes are transcriptionally regulated by Dorsal and are differentially expressed along the dorsoventral axis in distinct domains. Several of the identified genes encode transcription factors that may function together with Dorsal to control patterning of gene expression along the dorsoventral axis. Our initial results on Dorsal- dependent target gene expression also raise a number of questions regarding threshold outputs of gene expression. In particular, how is the expression of Dorsal target genes spatially restricted to distinct domains along the dorsoventral axis and do transcription factors that were identified in the microarray screen function together with Dorsal to control patterning? We have proposed two specific aims to address these questions: (1) to identify transcription factors that function together with Dorsal through enhancer analyses (using cis- regulatory motifs we have identified are important for expression), and (2) to characterize the function of two putative transcription factors which we propose contribute to patterning of the embryo (Neu2, identified by our microarray studies, and Wek, a maternally expressed gene identified in a genetic screen). Characterization of the mechanisms used by these transcription factors to affect differential gene expression n distinct domains will provide generally applicable insights into the regulation of gene expression controlled Dy morphogen gradients. These studies may also provide insights into transcriptional regulation by Rel transcription factors in general, and therefore have the potential to provide far-reaching implications into processes regulated by NFkappaB including the immune response, cancer, and allergic inflammation .