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

几乎所有的动物都表现出某种形式的前后（头到尾）轴的分割。人体平面分割的一个例子是脊柱；每个椎体代表一个单独的节段，具有独特的结构或形态。我对两个一般性问题感兴趣：首先，如何建立正常的段数；其次，一个片段如何被赋予一个独特的形态？为了严格解决这个问题，我使用了果蝇昆虫模型系统，其中身体计划沿着前后轴分为14个节段单位（parasegments）。果蝇的fushi tarazu基因（ftz）编码的ftz蛋白决定发育过程中形成的片段数量，而proboscipedia （pb）和Sex comb reduced （Scr）基因编码的pb和Scr蛋白单独或共同决定3个片段（上颌、唇和第一胸）的独特身份。这三种蛋白质共享一个称为同源结构域（HD）的dna结合蛋白结构域。含hd蛋白（HOX）是调节基因转录的转录因子，这一过程将存储在DNA中的信息转化为可以被蛋白质合成机器读取的RNA。尽管许多受FTZ、PB和SCR调控的基因已经被鉴定并广泛表征，但对于这些转录因子是如何引起基因转录模式变化的，我们还缺乏了解。缺乏的一个关键因素是对这些蛋白质的功能域结构的完整描述。HOX转录因子已经被分析了20多年，但其功能域的定位一直很困难。近年来，我的课题组和其他人发现含有hd的蛋白质是由小的肽基序组成的，对整体活性的贡献很小。我们感兴趣的是更深入地剖析这些小基序在发育中的作用。这些知识将极大地增强我们对昆虫身体结构分割背后的机制逻辑的理解，并且由于HOX蛋白也用于脊椎动物（人类）身体结构的分割，因此这项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蛋白是转录因子的例子，这项在果蝇中的工作提供了对控制基因表达机制的一般生物学意义和应用的重要见解。因为，当你环顾自然世界时，是基因表达的控制使草变绿，血变红，水仙花变黄；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.