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

阐明斑马鱼鳍生长和再生过程中产生图案和形状的机制

• 批准号: 10698173
• 负责人: Sarah Kelly McMenamin
• 金额: $ 39.13万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-07 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698173
• 关键词: Adult; Advanced Development; Amputation; Behavior; Biological; Biology; Cell physiology; Cells; Characteristics; Clinical; Complex; Congenital Disorders; Development; Diagnosis; Disease; Excision; Experimental Models; Growth; Intervention; Knowledge; Length; Limb structure; Location; Logic; Modeling; Morphogenesis; Morphology; Natural regeneration; Nature; Organ; Organ Size; Pathway interactions; Pattern; Phenotype; Positioning Attribute; Regenerative Medicine; Research; Research Personnel; Shapes; Structure; System; Tail; Testing; Thyroid Hormones; Tissues; Zebrafish; appendage; imprint; malformation; member; mutant; novel; preservation; prevent; programs; regenerative therapy; skeletal; tool

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.

项目概要/摘要 发育（或再生）附肢中的组织必须正确解释它们在生物空间中的位置， 并使用该位置信息来了解生长过程中的大小、图案和形状的相对变化。 细胞在发育过程中解释其位置可能会导致附属物表型的衰弱变化， 此外，再生能力需要组织记忆或重新解释。 位置认同，然后重新部署这些信息来指导再生，尽管具有令人难以置信的相关性。 对于基础生物学和生物医学来说，人们仍然对空间环境如何调节局部环境知之甚少。 塑造生长器官的模式和形状的形态发生过程。 脊椎动物附肢的位置认同可以进一步努力预防、诊断和治疗先天性肢体 疾病，并且对于开发先进的再生疗法是必要的。 斑马鳍是研究生长和再生机制的强大系统，尾部（尾巴） 在截肢或切除任何部分后，鳍具有优雅、简单但信息丰富的结构。 器官、鳍迅速再生以再现原始大小、图案和形状。 几十年来，在关系管理机制取得重要进展的过程中，坦特一直是至关重要的工具。 鳍片尺寸。鳍片长度表型保留了鳍片结构的比例图案和整体形状—— 事实上，长度是形态学的唯一方面，在此之前还没有进行过实验。 破坏鳍射线图案或鳍的分叉形状的模型，而缺乏实验工具意味着 基本上对于模式和形状是如何建立或记忆的一无所知。 在这项提案中，研究人员引入了新颖的表型，其中图案和形状与 鳍的大小；这些工具将用于识别位置身份的途径和细胞过程 该团队最初将重点关注骨骼图案形成的机制。 鳍条的近远端轴，利用甲状腺激素调节相对射线极性的发现。 搜索者接下来会问身份是如何在中横轴上印记的。该团队开发了一个系统。 其中成虫永远不会形成中央裂口，并且会长成三角形而不是叉形。 该表型将用于测试幼虫 Shh 表达调节相对形态发生的模型 研究人员将明确地预测器官最终的分叉形状。 识别构成位置同一性模块的细胞状态，调节大小、图案和形状—— 整体鳍形态的三个基本特征总而言之，所提出的研究将开辟新的视野。 对于更广泛的领域，利用新的范例，通过位置认同的不同方面可以提供信息 这些进展有望贡献与发育相关的基础知识。 先天性疾病的临床干预，对于为再生医学奠定基础至关重要。