Regulation of Appendage Regeneration in Zebrafish

成年硬骨鱼和尾鱼两栖动物可以再生整个被截肢的附肢。相反， 成年哺乳动物肢体的再生修复仅限于指尖。面临的主要挑战之一 发育生物学是为了了解组织再生是如何发生的以及为什么发生的。肢体或鳍的特征 再生是形成胚泡，这是一种含有新骨骼祖细胞的间充质结构 元素。随着再生的进行，胚泡细胞的增殖和图案化受到调控，以至于丢失 正确大小和形状的组织将被替换。而定义的细胞动力学和分子目录 组织再生的因素正在扩大，我们对基因如何参与再生事件知之甚少 都是在受伤的情况下进行的。也就是说，招募基因激活者(或抑制者)的DNA序列是什么 在组织再生过程中，这些序列是如何在整个基因组中分布的 具有再生能力的动物，以及哪些转录因子参与了这些序列？ 最近，我们发现了一类优先激活基因表达的远端基因调控元件。 在再生过程中，可以在简单的结构中进行工程，以表达促进 再生，并有可能被远距离物种的转录机制识别。这个 这项提案的总体目标是发现基因调控概念和机制，以恢复大小和 被截肢的附肢的图案。我们将检验增强器和消音器元件至关重要的假设 允许斑马鱼附肢再生的调节模块。这项工作将增加对 脊椎动物组织再生过程中的发育调控，为 理解--也许是改变--人类组织再生能力的现有限制。

Adult teleost fish and urodele amphibians can regenerate entire amputated appendages. By contrast, regenerative healing of adult mammalian limbs is limited to the very tips of digits. One of the key challenges in developmental biology is to understand how and why tissue regeneration occurs. The hallmark of limb or fin regeneration is formation of a blastema, a mesenchymal structure that contains progenitor cells for new skeletal elements. As regeneration proceeds, blastemal cell proliferation and patterning are regulated such that lost tissues of correct size and shape are replaced. While the catalogue of defined cell dynamics and molecular factors in tissue regeneration is expanding, we know much less of how genes involved in regenerative events are engaged upon injury. That is, what are the DNA sequences that recruit activators (or repressors) of gene programs during tissue regeneration, how are these sequences distributed throughout the genomes of regeneration-competent animals, and what are the transcription factors that engage with these sequences? Recently, we identified a class of distal gene regulatory elements that preferentially activate gene expression during regeneration, can be engineered in simple constructs to express developmental factors that promote regeneration, and have the potential to be recognized by the transcriptional machinery of distant species. The overall goal of this proposal is to discover gene regulatory concepts and mechanisms that restore size and pattern to an amputated appendage. We will test the hypothesis that enhancer and silencer elements are crucial regulatory modules enabling appendage regeneration in zebrafish. This work will increase understanding of developmental regulation during vertebrate tissue regeneration, and provide important perspective for comprehending, and perhaps changing, the existing limitations in regenerative capacity of human tissues.