Hox Regulation of Sensory Organ Development in Drosophila

描述（申请人提供）：细胞如何解释位置信息以正确分化并形成不同的组织和器官是发育生物学的一个基本问题。例如，在神经系统中，许多神经元亚型和感觉器官在精确定义的位置形成。本研究的长期目标是了解由Hox转录因子提供的前后位置信息如何与神经元分化途径相结合，从而决定体内不同神经元和感觉器官的类型、数量和位置。以果蝇为模型生物，我们专注于了解一种特殊的Hox因子Abd-A （Abd-A）如何通过激活菱形体（rho）来调节感觉器官的形成。rho编码一种蛋白酶，该蛋白酶处理表皮生长因子（EGF）配体以诱导额外的神经元和一组肝细胞样细胞。通过生物信息学和转基因报告分析，我们确定了两个在腹部感觉神经元的特定亚群中表达的hox调节的rho增强子。保守增强子区域的生化和遗传特征揭示了Hox因子及其保守的辅助因子extraenticle （Exd）和Homothorax （Hth）刺激基因表达的新机制：Abd- a通过直接竞争DNA结合位点拮抗神经元锌指蛋白Sens （Sens）的转录抑制。Sens及其脊椎动物同源物生长因子独立-1 （Growth factor independence-1, Gfi1）是果蝇和小鼠感觉器官发育的关键调控因子。我们假设Hox-Sens拮抗是基因调控的一般机制。这一假设以及其他Hox-神经元转录因子相互作用的鉴定将在以下目标中得到验证：1)确定Abd-A刺激rho的机制，2)测试Hox- Sens竞争在基因表达调控中的作用，以及3)确定ch器官SOP细胞中调节rho的其他神经元输入。这些实验利用了果蝇的遗传工具，与脊椎动物不同，果蝇包含一组非冗余的Hox因子。除了控制神经元发育外，Hox、Exd、Hth和Sens脊椎动物同源基因都调节血细胞形成，并与白血病有关。因此，在这项资助中发现的Hox和Sens/Gfi1分子机制与人类发育和疾病有关。

DESCRIPTION (provided by applicant): How cells interpret positional information to properly differentiate and form distinct tissues and organs is a fundamental problem in developmental biology. In the nervous system, for example, numerous neuronal subtypes and sensory organs form at precisely defined positions. The long-term goal of this proposal is to understand how anterior- posterior positional information provided by Hox transcription factors is combined with neuronal differentiation pathways to dictate the type, number, and location of different neurons and sensory organs in the body. Using Drosophila as a model organism, we are focused on understanding how a specific Hox factor, Abdominal-A (Abd-A), modulates sensory organ formation by activating rhomboid (rho). rho encodes a protease that processes an epidermal growth factor (EGF) ligand to induce additional neurons and a set of hepatocyte-like cells. Through bioinformatics and transgenic reporter assays, we identified two Hox-regulated rho enhancers expressed in a specific subset of abdominal sensory neurons. The biochemical and genetic characterization of a conserved enhancer region uncovered a novel mechanism used by Hox factors and their conserved co-factors Extradenticle (Exd) and Homothorax (Hth) to stimulate gene expression: Abd- A antagonizes transcriptional repression by Senseless (Sens), a neuronal zinc finger protein, through direct competition for DNA binding sites. Sens and its vertebrate homologues Growth factor independence-1 (Gfi1) are critical regulators of sensory organ development in both the fly and mouse. We hypothesize that Hox-Sens antagonism is a general mechanism of gene regulation. This hypothesis as well as the identification of other Hox-neuronal transcription factor interactions will be tested in the following aims: 1) Determine the mechanisms used by Abd-A to stimulate rho, 2) Test the role of Hox- Sens competition in the regulation of gene expression, and 3) Identify additional neuronal inputs that regulate rho in ch organ SOP cells. These experiments take advantage of genetic tools available in Drosophila, which unlike in the vertebrate, contain a single set of non-redundant Hox factors. In addition to controlling neuronal development, the Hox, Exd, Hth, and Sens vertebrate homologues all regulate blood cell formation and have been implicated in leukemia. Thus, the Hox and Sens/Gfi1 molecular mechanisms uncovered in this grant are relevant to human development and disease. Public Health Relevance: We have identified two factors that regulate nervous and blood system development. This grant is focused on how these factors function to specify sensory organs using the fruit fly as a model system. As both factors have been implicated in leukemia, our studies are likely to shed new insight into both Human development and disease.