Regulation of Shh Signaling Activity in Limb Patterning

肢体模式中 Shh 信号活动的调节

• 批准号: 7630604
• 负责人: CHIN CHIANG
• 金额: $ 32.67万
• 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/7630604
• 关键词: Address; Affect; Behavior; Biological; Biological Process; Cells; Chin; Cholesterol; Clinical; Complex; Digit structure; Disease; Dose; Elements; Embryo; Environment; Equilibrium; Erinaceidae; Family; Gene Family; Genes; Genetic Transcription; Goals; Growth; Holoprosencephaly; Human; Integral Membrane Protein; Invertebrates; Knowledge; LIM Domain; Length; Ligands; Limb Bud; Limb Development; Limb structure; Lipids; Malignant Neoplasms; Mediating; Modification; Movement; Mus; Mutation; N-terminal; Organogenesis; Paracrine Communication; Pattern; Pattern Formation; Play; Process; Proteins; Regulation; Relative (related person); Research Personnel; Role; Series; Shapes; Signal Transduction; Site; Specific qualifier value; Tissues; Transcription Coactivator; extracellular; genome wide association study; morphogens; mutant; paracrine; programs; protein distribution; receptor; s-ShhNp; skeletal

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）：由Hedgehog（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生长和模式形成的关键信号。编码Shh信号传导组分的Shh基因的突变与人类中发现的许多临床疾病相关，包括前脑无裂畸形和各种形式的癌症。Hh配体的最显著特征之一是在发育组织中充当经典形态原的能力。这在发育中的脊椎动物肢体中特别明显，其中Shh通常在极化活动区（ZPA）的后肢边缘中表达，具有以剂量依赖性方式逐渐指定具有更多后部身份的手指数量增加的能力。此前，我们的研究确定了Shh在肢体骨骼元素的生长和图案形成中的要求。此外，我们表明，这一要求是必要的调节Gli 3处理介导的。在这种情况下，从ZPA分泌的Shh抑制Gli 3加工成其阻遏物形式（GN 3R），因此促进全长GN 3蛋白（Gli 3- FL或GH 3 -190）的积累，其可以在Shh信号传导范围内充当转录激活物（GN 3A），因此，GN 3A和GN 3R之间的相对平衡可能在介导Shh的肢体图案功能中起关键作用。在理解Shh活动梯度如何调节以在肢体中产生定义的模式方面仍然存在重大差距。解决这个问题需要更好地了解影响Shh运动的因素，配体-受体相互作用，旁分泌活动的模式化效应，以及响应组织中效应子的转录活性。因此，我们提出的研究主要旨在通过解决（1）胆固醇部分在哺乳动物组织环境中调节Shh运动/空间范围的作用，（2）局部和旁分泌信号在产生复杂的数字模式中的作用，（3）不同形式的Gli 3在调节组织图案形成中的生物学功能。我们相信这些知识将直接关系到Shh在人类器官形成、疾病和癌症中的作用。