DAP-2 Regulation By Notch In Drosophila Leg Development

果蝇腿部发育中 DAP-2 的调控

基本信息

批准号：
6709327
负责人：
PAMELA J MITCHELL
金额：
$ 21.98万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至 2006-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): A central goal of developmental biology is to understand the gene expression programs and signal transduction pathways that regulate cell fate decisions and cellular differentiation in developing tissues. The long-term objective of our research is to investigate the developmental regulation and functions of AP-2 transcription factors. In mammals, AP-2 family members (AP-2a, AP-2/3 and AP-2g) have essential roles in development and are implicated as tumor suppressors in breast and ovarian carcinomas and melanoma. We identified dAP-2, the sole Drosophila melanogaster homolog of mammalian AP-2 family genes, in order to use the versatile tools of Drosophila genetics to establish regulatory paradigms for AP-2. Our recent unpublished data including analysis of dAP-2 null and partial loss of function mutants and analysis of dAP-2 expression in leg imaginal discs mosaic for mutations in various Notch signaling components, lead us to hypothesize that dAP-2 is a critical target of Notch signaling during leg and central nervous system development. The nervous system defects, reduced proboscis and severely shortened legs of dAP-2 null mutant flies correlate strikingly with nervous system, craniofacial, and limb defects seen in AP-2cx knock-out mice indicating that AP-2 family functions have been fundamentally conserved between flies and mice. We propose to examine the dependency of dAP-2 expression on Notch signaling in the limb imaginal disc during larval and pupal stages and in procephalic neuroectoderm during embryogenesis using a combination of genetic and molecular approaches including loss- and gain-of-function genetic analyses, immunostaining, and mapping of dAP-2 cis regulatory elements. The proposed research will significantly advance our understanding of AP-2 regulation during limb and nervous system development, and refine our understanding of how Notch signaling is interpreted in different tissues. In addition this work may shed light on how mis-regulation of AP-2 factors contributes to loss of growth control leading to cancer.

描述（由申请人提供）：发育生物学的中心目标是了解基因表达程序和信号转导途径调节发育过程中的细胞命运决定和细胞分化组织。我们研究的长期目标是调查 AP-2转录因子的发育调控和功能。在对于哺乳动物来说，AP-2 家族成员（AP-2a、AP-2/3 和 AP-2g）在发育并被认为是乳腺癌和卵巢的肿瘤抑制因子癌和黑色素瘤。我们鉴定出 dAP-2，唯一的黑腹果蝇哺乳动物 AP-2 家族基因的同源物，以便使用多功能工具果蝇遗传学建立 AP-2 的调控范式。我们最近的未发表的数据，包括 dAP-2 无效和部分功能丧失的分析腿成虫盘嵌合体中 dAP-2 的突变体和表达分析各种Notch信号成分的突变使我们推测 dAP-2 是腿部和中枢神经系统中 Notch 信号传导的关键靶点系统开发。神经系统缺陷，长鼻缩小，严重 dAP-2无效突变果蝇的腿缩短与神经紧张显着相关 AP-2cx 敲除小鼠中观察到的系统、颅面和肢体缺陷表明 AP-2 家族功能在果蝇和老鼠。我们建议检查 dAP-2 表达对 Notch 的依赖性在幼虫和蛹阶段以及在胚胎发生过程中的前头神经外胚层使用遗传组合和分子方法，包括功能丧失和获得的遗传分析，免疫染色和 dAP-2 顺式调控元件图谱。拟议的研究将显着增进我们对 AP-2 调控的理解肢体和神经系统发育，并完善我们对 Notch 的理解信号传导在不同的组织中被解释。另外这项工作可能会流阐明 AP-2 因子的错误调节如何导致生长损失控制导致癌症。