Illuminating the mechanisms that generate pattern and shape during growth and regeneration of the zebrafish fin

项目总结/摘要 发育（或再生）附肢中的组织必须正确地解释它们在生物空间中的位置， 并使用该位置信息来告知生长期间的尺寸、图案和形状。相对变化如何 细胞在发育过程中解释它们的位置可导致附属器表型的削弱性变化， 包括肢体畸形此外，再生能力需要组织记住或重新解释 位置标识，然后重新部署此信息以指导重新生长。尽管如此， 对于基础生物学和生物医学来说，空间背景如何调节局部环境仍然知之甚少。 塑造生长器官的模式和形状的形态发生过程。了解的性质 脊椎动物附肢的位置一致性可以进一步预防、诊断和治疗先天性肢体畸形 疾病，并将是必要的发展先进的再生疗法。 斑马鱼鳍是研究生长和再生机制的强大系统，尾部（尾巴） Finn拥有一个优雅，简单但信息丰富的结构。在截肢或切除任何部分后， 在器官中，鳍迅速再生以重现原始大小，图案和形状。长鳍和短鳍母- 几十年来，在实现关系管理机制方面取得了重要进展， 定的大小。鳍长度表型保持了鳍结构的比例模式和整体形状- 长度是形态学改变的唯一方面。事实上，在此之前，还没有实验性的 模型来破坏鳍射线图案或鳍的分叉形状，这种缺乏实验工具的情况意味着 我们对图案和形状是如何建立或记忆的基本上一无所知。 在这项提议中，研究人员引入了新的表型，其中图案和形状与 这些工具将用于识别位置识别的途径和细胞过程 和形态的形成该小组将首先集中在骨骼模式的机制，沿着 鳍射线的近端-远端轴，利用甲状腺激素调节相对射线极性的发现。再- 搜索者接着问身份是如何在中-横向轴上被印记的。该团队开发了一个系统 在那里，成年鳍从未发展出中央裂缝，并成长为三角形，而不是分叉的形状。 该表型将用于测试幼虫Shh表达调节相对形态发生的模型。 在鳍状褶皱上的行为，以预先形成器官的最终分叉形状。研究人员将明确 识别构成调节大小、图案和形状的位置同一性模块的细胞状态， 整体鳍形态的三个基本特征。总而言之，拟议中的研究将开辟新的视野 对于更广泛的领域，利用新的范式，通过这些新范式，位置认同的不同方面可以为 形态发生这些进展预计将有助于发展相关的基础知识 先天性疾病的临床干预，并在奠定再生医学的基础至关重要。

PROJECT SUMMARY/ABSTRACT Tissues in a developing (or regenerating) appendage must correctly interpret their location in biological space, and use this positional information to inform size, pattern and shape during outgrowth. Relative changes in how cells interpret their positions during development can lead to debilitating changes in appendage phenotype, including limb malformations. Further, the ability to regenerate requires that tissues remember or reinterpret positional identity, then re-deploy this information to guide regrowth. Nonetheless, despite incredible relevance to both basic biology and biomedicine, it remains poorly understood how spatial context regulates the local morphogenetic processes which sculpt the pattern and shape of growing organs. Understanding the nature of positional identity in vertebrate appendages can further efforts to prevent, diagnose and treat congenital limb disorders, and will be necessary for development of advanced regenerative therapies. Zebrafish fins are a powerful system for studying mechanisms of growth and regeneration, and the caudal (tail) fin possesses an elegant, simple-yet-informative structure. After amputation or removal of any portion of the organ, fins regenerate rapidly to reproduce the original size, patterning and shape. Long- and short-finned mu- tants have served as crucial tools in decades of important progress towards the mechanisms regulating rela- tive fin size. Fin length phenotypes preserve the proportional patterning and overall shape of the fin structure— length is the only aspect of morphology that is altered. Indeed, before now, there have not been experimental models to disrupt fin ray patterning or the forked shape of the fin, and this lack of experimental tools means that essentially nothing is known about how pattern and shape are established or remembered. In this proposal, researchers introduce novel phenotypes in which patterning and shape are decoupled from size in the fin; these tools will be used to identify pathways and cellular processes underlying positional identity and the morphogenesis of form. The team will initially focus on mechanisms of skeletal patterning along the proximo-distal axis of fin rays, using the discovery that thyroid hormone regulates relative ray polarity. The re- searchers next ask how identity is imprinted across the medio-lateral axis. The team has developed a system in which the adult fin never develops a central cleft, and grows into a triangular rather than a forked shape. This phenotype will be used to test a model in which larval Shh expression regulates relative morphogenetic behaviors across the fin fold to pre-pattern the eventual forked shape of the organ. Researchers will explicitly identify the cell states that constitute modules of positional identity regulating size, patterning and shape—the three essential characteristics of overall fin morphology. In all, the proposed research will open fresh horizons for the broader field, leveraging new paradigms by which different aspects of positional identity can inform morphogenesis. These advances are expected to contribute foundational knowledge relevant in developing clinical interventions for congenital disorders, and critical in laying the groundwork for regenerative medicine.