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地分化和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。这一建议的长期目标是了解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，以决定不同神经元和感官在体内的类型、数量和位置。以果蝇为模型生物，我们致力于了解一种特定的HOX因子，腹型A(Abd-A)是如何通过激活菱形(Rho)来调节感觉器官的形成。Rho编码一种蛋白酶，处理表皮生长因子(EGF)配体，诱导更多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基因分析，我们鉴定了两个受HOx调控的Rho增强子，它们在特定的腹部感觉神经元亚群中表达。对一个保守的增强子区域的生物化学和遗传学特征揭示了HOX因子及其保守的辅助因子牙外环(EXD)和同胸(HTH)用来刺激基因表达的新机制：ABD-A通过直接竞争DNA结合位点来对抗无感觉(SENS)转录抑制。SENS及其脊椎动物同系物生长因子独立性-1(GFI1)是苍蝇和小鼠感觉器官发育的关键调节因子。我们假设Hox-Sens拮抗是基因调控的一般机制。这一假说以及其他Hox-神经元转录因子相互作用的鉴定将在以下目的进行验证：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)确定在CH器SOP细胞中调节Rho的额外神经元输入。这些实验利用了果蝇可用的遗传工具，与脊椎动物不同，果蝇包含一组非冗余的HOX因子。除了控制神经元的发育，脊椎动物的HOX、EXD、HTH和SENS同系物都调节血细胞的形成，并与白血病有关。因此，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。 公共卫生相关性：我们已经确定了调节神经和血液系统发育的两个因素。这项资助的重点是这些因素如何发挥作用，以果蝇为模型系统来指定感官。由于这两个因素都与白血病有关，我们的研究很可能对人类发育和疾病都有新的见解。

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.