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

项目摘要/摘要 发育中(或再生)附件中的组织必须正确地解释它们在生物空间中的位置， 并使用这种位置信息在生长过程中告知大小、图案和形状。方式的相对变化 细胞在发育过程中解释自己的位置会导致附肢表型的衰弱变化， 包括肢体畸形。此外，再生的能力需要组织记住或重新解释 位置身份，然后重新部署此信息以指导再生。尽管如此，尽管关联性令人难以置信 对于基础生物学和生物医学来说，空间背景如何调节局部仍然知之甚少。 塑造生长器官的图案和形状的形态发生过程。理解的本质 脊椎动物附肢的位置识别可以进一步努力预防、诊断和治疗先天性肢体 这是治疗精神障碍的重要手段，也是开发先进的再生疗法所必需的。 Zebrafishfins是一个研究生长和再生机制的强大系统，尾部(尾部) fin拥有一种优雅、简单但信息丰富的结构。在截肢或移除任何部分 器官，fins迅速再生，以复制原始的大小、图案和形状。Long-fi和Short-Nned Mu- 在几十年来朝着调节关系的机制取得重要进展的过程中，试剂一直是至关重要的工具。 Activefin大小。鳍长表型保持了fin结构的比例图案和整体形状- 长度是形态唯一被改变的方面。事实上，在此之前，还没有试验性的 破坏fin射线图案或fin叉形的模型，而这种缺乏实验工具意味着 从本质上讲，我们对图案和形状是如何建立或记住的一无所知。 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 fin中的大小；这些工具将用于识别潜在的位置认同的路径和细胞过程 以及形式的形态发生。该团队最初将专注于骨骼图案沿线的机制 fin射线的近远轴，利用甲状腺激素调节相对射线极性的发现。再一次- 搜索者接下来会问，身份是如何在中轴线上留下印记的。该团队已经开发出一种系统 在这种情况下，成年的fin永远不会形成中央裂隙，而是生长成三角形而不是叉形。 这种表型将被用来测试幼虫Shh表达调节相对形态发生的模型 跨越fi的行为n倍，以预制器官最终的分叉形状。研究人员将明确表示 识别构成调节大小、图案和形状的位置同一性模块的单元状态- 总体fin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field，利用位置认同感的不同方面可以提供信息的新范式 形态发生。这些进展有望贡献与开发相关的基础知识 先天疾病的临床干预，以及为再生医学奠定基础的关键。

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.