Functional dissection of Drosophila homeodomain transcription factors required for development of the body plan.

几乎所有的动物都会在前后(头到尾)轴上表现出某种形式的节段。人体平面的节段的一个例子是脊椎；其中每个脊椎代表一个单独的节段，具有独特的结构或形态。我感兴趣的是两个一般性的问题：第一，节段的正常数量是如何建立的；第二，一个节段如何被分配一个独特的形态？为了严格地解决这个问题，我使用了果蝇(果蝇)昆虫模型系统，其中身体平面沿着前后轴被划分为14个节段单位(副节段)。果蝇、福氏和蜘蛛基因(FTZ)编码一种蛋白质FTZ，用于确定在发育过程中形成的节段的数量，以及鼻脚(PB)和性梳子减少(SCR)基因编码蛋白质PB和SCR，这两个蛋白单独或共同作用来确定3个节段(上颌、唇部、这三种蛋白质都有一个DNA结合的蛋白质结构域，称为同源结构域(HD)。含HD蛋白(HOX)是调节基因转录的转录因子，是将储存在DNA中的信息转化为蛋白质合成机制可以读取的RNA的过程。尽管许多受HDFZ、PB和SCR调控的基因已经被识别和广泛表征，但对于这些转录因子如何导致基因转录模式的变化仍然缺乏了解。一个关键因素是对这些蛋白质的功能结构域结构的完整描述。HOX转录因子被分析了20多年，但功能结构域的绘制被证明是困难的。近年来，我的团队和其他人已经发现，含有HD的蛋白质是由对整体活动做出微小贡献的小肽和基序组成的。我们有兴趣更深入地剖析这些小基序在发育中的作用。这些知识将极大地提高我们对昆虫身体平面分割背后的机理和逻辑的理解，由于Hox蛋白也用于脊椎动物(人类)身体平面的分割，这项研究工作对理解一般的发育过程具有普遍的应用价值。此外，由于Hox蛋白质是转录因子的例子，这项在苍蝇身上的工作提供了具有普遍生物学意义的重要见解和控制基因表达的机制的应用。因为，当你环顾自然界时，是基因表达的控制使草绿、血红、水仙黄；基因表达的控制是所有生物学的基础。

Nearly all animals exhibit some form of segmentation along the anterior-posterior (head to tail) axis.  An example of segmentation of the human body plan is the backbone; where each vertebra represents an individual segment and has a unique structure or morphology.  I am interested in two general questions: first how the normal number of segments is established; and second how a segment is assigned a unique morphology?  To address this rigorously, I use the Drosophila melanogaster (fruit fly) insect model system where the body plan is divided into 14 segmental units (parasegments) along the anterior-posterior axis.  The Drosophila fushi tarazu gene (ftz) encodes a protein FTZ required for determining the number of segments that form during development, and the proboscipedia (pb) and Sex combs reduced (Scr) genes encode proteins PB and SCR that work alone or together to determine the unique identities of 3 segments (maxillary, labial, and first thoracic).  All three proteins share a DNA-binding protein domain called the homeodomain (HD).  HD-containing proteins (HOX) are transcription factors that regulate the transcription of genes, the process that converts information stored in DNA to RNA that can be read by the protein synthesis machinery.  Even though many of the genes regulated by FTZ, PB and SCR have been identified and extensively characterized, there is a lack of knowledge about how these transcription factors work to bring about changes in the pattern of gene transcription.  One key element lacking is a complete description of the functional domain structure of these proteins.  HOX transcription factors have been analyzed for over twenty years, but the mapping of the functional domains has proven difficult.  In recent years, my group and others have found that HD-containing proteins are composed of small peptide motifs that make small contributions to overall activity.  We are interested in a deeper dissection of the roles of these small motifs in development. This knowledge will greatly enhance our understanding of the mechanistic logic behind the segmentation of the insect body plan, and as HOX proteins are also used during the segmentation of the vertebrate (human) body plan, this work has general application to the understanding of the developmental process in general.  Furthermore, as HOX proteins are examples of transcription factors, this work in flies provides important insights of general biological significance and application on mechanisms that control gene expression.  Since, when you look around at the natural world it is the control of gene expression that makes the grass green, blood red and daffodils yellow; the control of gene expression is fundamental to all Biology.