Regulation of Shh Signaling Activity in Limb Patterning

肢体模式中 Shh 信号活动的调节

• 批准号: 7145045
• 负责人: CHIN CHIANG
• 金额: $ 31.32万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145045
• 关键词: biological signal transduction; bone development; cholesterol; developmental genetics; embryo /fetus; gene deletion mutation; gene expression; gene induction /repression; genetic regulation; genetic transcription; genetically modified animals; laboratory mouse; ligands; limbs; membrane proteins; molecular polarity; paracrine; protein localization; protein protein interaction; protein structure function; protein transport; sonic hedgehog gene /protein; transcription factor

DESCRIPTION (provided by applicant): Secreted molecules encoded by the Hedgehog (Hh) gene family have been recognized as key signals in regulating the growth and patterning of invertebrate and vertebrate embryos. Mutations in Shh genes encoding Shh signaling components have been associated with many clinical disorders found in humans including holoprosencephaly and various forms of cancer. One of the most salient features of Hh ligands is the ability to act as a classical morphogen in developing tissues. This is particularly evident in the developing vertebrate limbs, where Shh, normally expressed in the posterior limb margin of the zone of polarizing activity (ZPA), has ability to progressively specify increase in number of digits with more posterior identities in a dose-dependent manner. Previously, our studies identified the requirements of Shh in both growth and patterning of the skeletal elements of the limb. Additionally, we showed that this requirement is necessarily mediated by regulation of Gli3 processing. In this context, Shh secreted from the ZPA inhibits Gli3 processing into its repressor form (GN3R), hence promoting the accumulation of full-length GN3 protein (Gli3- FL or GH3-190), which can function as a transcriptional activator (GN3A) within the range of Shh signaling, thus, the relative balance between GN3A and GN3R likely plays a critical role in mediating the limb patterning function of Shh. Major gaps remain in understanding how the Shh activity gradient is regulated to generate defined patterns in the limb. Addressing this question requires a better understanding of factors affecting Shh movement, ligand-receptor interaction, patterning effects of paracrine activity, and transcriptional activity of effectors in the responsive tissue. Therefore, our proposed studies are aimed primarily at providing a better understanding of how Shh signaling is regulated and interpreted during limb development by addressing (1) the role of cholesterol moiety in regulating Shh movement/spatial range in a mammalian tissue environment, (2) the contribution of local and paracrine signaling in generating a complex pattern of digits, (3) the biological function of different forms of Gli3 in regulating tissue patterning. We believe this knowledge will be directly relevant to the role of Shh in human organogenesis, disease and cancer.

描述（由申请人提供）：刺猬（HH）基因家族编码的分泌分子已被认为是调节无脊椎动物和脊椎动物胚胎的生长和模式的关键信号。编码SHH信号成分的SHH基因中的突变与人类中的许多临床疾病有关，包括全脑脑和各种形式的癌症。 HH配体最显着的特征之一是能够充当发展组织中的经典形态。这在发育中的脊椎动物四肢中尤其明显，在脊椎动物的四肢中，通常在极化活性区域（ZPA）的后肢边缘表达的SHH具有逐渐依赖性方式具有更高后身份的数字数量逐渐指定数字数量的能力。以前，我们的研究确定了SHH在肢体骨骼元素的生长和模式中的要求。此外，我们表明该需求必然是由GLI3处理的调节介导的。在这种情况下，从ZPA分泌的SHH将GLI3加工抑制为其抑制剂形式（GN3R），因此促进了全长GN3蛋白（GLI3-FL或GH3-190）的积累，它们可以作为转录激活因子（GN3A）起作用。因此，在SHH信号传导的范围内，GN3A和GN3R之间的相对平衡可能在介导SHH的肢体图案函数中起关键作用。在理解如何调节SHH活性梯度以在肢体中生成定义的模式的主要差距。解决这个问题需要更好地理解影响SHH运动，配体 - 受体相互作用，旁分泌活性的模式效应以及响应组织中效应子的转录活性的因素。因此，我们提出的研究主要是为了更好地了解如何通过解决胆固醇部分在调节哺乳动物组织环境中SHH运动/空间范围中的作用（1）在肢体发育过程中如何调节和解释SHH信号的作用，（2）局部和旁分泌信号在产生复杂的数字模式中的贡献，（3）不同形式的GLI3在调节组织模式下的生物学功能。我们认为，这些知识将与SHH在人体器官发生，疾病和癌症中的作用直接相关。