Collaborative Research: NSF-BSF: How cell adhesion molecules control neuronal circuit wiring: Binding affinities, binding availability and sub-cellular localization

神经系统的感觉和运动功能依赖于发育过程中不同类型的神经元和靶细胞之间精确连接的建立。在脊椎动物和无脊椎动物发育中的神经系统中，神经元表达多种细胞粘附分子，这些细胞粘附分子介导相互作用，对于指定目标选择和连接模式至关重要。本课题将通过遗传和生物物理相结合的方法研究神经回路发育的分子调控，通过调控细胞粘附分子的结合亲和力和细胞表面定位，研究其对果蝇幼虫神经回路形成的影响。由于所研究现象的普遍性，本研究将对多个研究领域产生重大影响。此外，将计算生物学和结构生物学与发育神经科学相结合，可能会在这些领域激发类似的合作努力。在训练方面，参与该项目的学生和博士后将对计算和实验工作有深刻的理解，从而为受过广泛训练的跨学科科学家提供范例。女性科学家占参与群体的50%以上。该研究项目包括通过暑期实习对高中生和本科生进行培训，其中许多学生来自科学界代表性不足的少数族裔。该团队将继续与低收入地区的高中网络和少数族裔大学合作，并为高中生开设DREAM-High云计算课程，提高学生对生物科学的认识和兴趣，使学生能够采用科学推理和批判性思维技能，并激励学生在相关领域寻求高等教育。本项目将研究细胞粘附分子（CAMs）的结合亲和力和细胞表面可用性对果蝇神经回路形成的影响。该研究将重点关注幼虫的神经肌肉系统和蘑菇体的发育。在分子水平上，重点将放在CAMs的两个相互作用组上，即Dprs（缺陷的喙延伸反应）和DIPs （Dpr相互作用蛋白）。这些蛋白质和解剖结构的选择是基于对过去几年出现的dip和Dprs生物物理特性的深刻理解，以及它们在这些解剖结构发展中的关键作用的证明。在这里，通过在不同的神经发育环境中检查各种Dpr/DIP同源对，研究结果应该加深目前有限的利用结合亲和力和表达水平改变亲和度的体内后果的知识。特别关注的将是顺式抑制现象，即同一细胞上同源结合伙伴之间的相互作用与对立细胞上的反式结合伙伴竞争。潜在的假设是顺式抑制是神经发育的关键调节机制。该项目由生物科学理事会IOS的神经系统集群和MCB的分子生物物理集群共同资助。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 sensory and motor functions of the nervous system depend on the establishment of precise connections between different types of neurons and target cells during development. In the developing nervous systems of both vertebrates and invertebrates, neurons express a wide diversity of cell adhesion molecules, which mediate interactions that are essential for specifying target selection and connectivity patterns. This proposal will study the molecular control of circuit development through a combination of genetic and biophysical approaches in which binding affinities and cell surface localization of cell adhesion molecules are manipulated and their effects on neural circuit formation are studied in the larva fruit fly. The proposed research will have a significant impact on multiple research fields due to the generality of the phenomena to be studied. Moreover, integrating computational and structural biology with developmental neuroscience is likely to stimulate similar collaborative efforts in these fields. In terms of training, students and postdocs working on this project will develop a deep appreciation of both computational and experimental work, thus providing exemplars for broadly trained interdisciplinary scientists. Women scientists constitute over 50% of the participating groups. The research program includes training of high school and undergraduate students, many of whom are from underrepresented minorities in sciences, through summer internships. The team will continue partnering with a network of high schools across lower-income districts and minority serving colleges, and run the DREAM-High cloud computing course for high school students that increases student awareness of and interest in biological sciences, empowers students to adopt scientific reasoning and critical-thinking skills, and inspires students to seek post-secondary education in related fields.This project will investigate the effects of binding affinity and cell surface availability of cell adhesion molecules (CAMs) on circuit formation in Drosophila. The study will focus on the larval neuromuscular system and mushroom body development. At the molecular level, the focus will be on two interacting groups of CAMs, the Dprs (Defective in Proboscis extension Response) and the DIPs (Dpr Interacting Proteins). The choice of these proteins and anatomical structures is based on the deep understanding of the biophysical properties of DIPs and Dprs that has emerged over the past few years, and on the demonstration of their crucial roles in the development of these anatomical structures. Here, by examining various Dpr/DIP cognate pairs in different neurodevelopmental settings, the findings should deepen currently limited knowledge of the in vivo consequences of altering avidity using both changes in binding affinities and in expression levels. A particular focus will be on the phenomenon of cis inhibition, whereby interactions between cognate binding partners on the same cell compete with trans binding to partners on apposed cells. The underlying hypothesis is that cis-inhibition is a key regulatory mechanism in neural development.This project is jointly funded by the Neural Systems Cluster in IOS and the Molecular Biophysics Cluster in MCB of the Directorate for Biological Sciences.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.