The developmental basis for sensory-skeletal integration: The osteo-inductive role of neuromasts

结构与功能统一的过程对于适应自然世界至关重要。这个过程的关键部分是将感觉结构（如眼睛）与相关结构（如头骨）连接起来。不同的器官系统在发育过程中相互连接的过程在很大程度上是未知的。该项目研究了感觉系统可能影响、指导和组织脊椎动物的面部和头骨的概念，这一现象在文献中一直被怀疑。古典研究人员发现，根据现存和灭绝的（化石）证据，感觉神经突似乎标志着骨骼未来的位置。了解器官系统是如何整合在一起的，对于理解控制适应的基本过程是必要的。提出的工作告知不同的生理系统如何在发育过程中相互作用，并提高我们对骨诱导的分子和发育基础的理解。这项工作将通过创造性的技术来完成，比如显微外科手术，这将使人们对这个经典问题有新的认识。拟议研究的更广泛影响将扩展现有的K-12课程，教授孩子们关于进化论的知识，促进国际合作和拓展机会，并为本科生和研究生提供指导，以发展成功的拓展活动。拟议的工作还为适应性遗传学提供了一个重要的案例研究，并为支持更广泛的Astyanax研究界的发展创造了资源。这个应用程序的科学目标是了解感觉和骨骼系统之间整合的发展基础。中心假设是感觉毛细胞器官（称为“神经肥大”）诱导面部特定区域的骨形成。这个问题将通过三个目标来解决。第一个目的是研究候选诱导分子在面部骨形成关键时期的基因表达模式，以及内皮素-1信号肽功能丧失的影响，内皮素-1信号肽是面部骨形成的关键分子。这些实验将确定在发育过程中诱导何时发生，以及诱导分子如何介导这种相互作用。第二个目标是通过实验移植解开神经鞘和骨骼之间的关系。完成后，这项工作将确定为什么只有某些管神经桅杆能够诱导骨，确定神经桅杆是否自主诱导骨形成，以及骨形态发生蛋白（BMP）信号传导是否介导“成骨”神经桅杆的诱导特性。第三个目标将确定实验性的感觉神经突的丧失如何影响面部骨的形成。本研究完成后，将在神经鞘内确定感应分子的细胞来源。此外，这项研究将确定神经突是否持续表达感应信号，周围组织是否必须能够对信号做出反应，或者两者兼而有之。通过这些研究活动，预计将在理解结构和功能如何协调执行基本生物过程方面取得重大进展。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The process of uniting structure with function is fundamentally important for adapting to the natural world. A key part of this process is connecting sensory structures (e.g. eyes) with relevant structures, like the skull. The process by which different organ systems become connected over the course of development is largely unknown. This project examines the notion that sensory systems may influence, direct and organize the face and skull of vertebrates, a phenomenon that has long been suspected in the literature. Classical researchers found that sensory neuromasts appeared to mark the future positions of bones, based on extant and extinct (fossil) evidence. Understanding how organ systems become integrated is necessary for understanding the fundamental processes governing adaptation. The proposed work informs how different physiological systems interact during development, and improves our understanding of the molecular and developmental bases for bone induction. This work will be performed through creative techniques, such as microsurgery, that will allow novel insight to this classic problem. The broader impacts of the proposed research will expand an established K-12 curriculum teaching children about evolution, promote collaboration and outreach opportunities internationally, and provide instruction for undergraduate and graduate students in developing a successful outreach activity. The proposed work also provides an essential case study for adaptive genetics, and creates resources to support growth of the broader Astyanax research community.The scientific objective of this application is to understand the developmental basis for integration between the sensory and skeletal systems. The central hypothesis is that sensory hair cell organs (called “neuromasts”) induce bone formation in specific regions of the face. This question will be approached via three aims. The first aim examines gene expression patterns of candidate induction molecules across the critical period of facial bone formation, and the impact of functional loss of the endothelin-1 signaling peptide, a key molecule for facial bone patterning. These experiments will determine when induction occurs during development, and how inductive molecules may mediate this interaction. The second aim disentangles the relationship between neuromasts and bones using experimental transplantation. When completed, this work will determine why only certain canal neuromasts are able to induce bone, determine if neuromasts induce bone formation autonomously, and if bone morphogenetic protein (BMP) signaling mediates the inductive properties of ‘osteogenic’ neuromasts. The third aim will determine how the experimental loss of sensory neuromasts impacts facial bone formation. Upon completion, this study will identify the cellular source within neuromasts of inductive molecules. Additionally, this study will determine if neuromasts continuously express an inductive signal, if the surrounding tissues must be able to respond to the signal, or both. Through these research activities, significant progress is expected towards understanding how structure and function are coordinated to execute essential biological processes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.