Using Drosophila to investigate the roles of conserved IgSF proteins in neuronal differentiation and axon guidance.

大脑正常运作的能力依赖于神经元的模式化发展和突触连接的受控建立。我们研究计划的总体目标是使用果蝇模型系统在分子和细胞水平上了解这些过程。我们正在研究外部信号如何通过免疫球蛋白超家族(IgSF)的三种跨膜蛋白(Ihog、Boi和Tutl)影响神经元的分化和轴突的引导。在这项探索助学金的前三年任期中，van Meyel实验室的学生们取得了令人兴奋的发现，表明Ihog、Boi和Tutl是神经元分化和/或轴突指导的关键调节因子。这些IgSF蛋白在包括哺乳动物在内的其他物种中都是保守的，它们由具有Ig样和纤维连接蛋白III型重复序列的胞外结构域、跨膜结构域和细胞质尾巴组成。我们最近发现，Ihog和Boi在功能上是多余的，对于Hedgehog(HH)途径的信号传递是必不可少的。HH是视网膜、脊髓、脑和许多其他细胞类型神经元分化的重要决定因素。我们还发现，Tutl是重要的轴突和树突的生长和引导模式，但其作用机制仍然是完全神秘的。本研究的具体目标是：1)确定Ihog和Boi如何参与Hedgehog信号通路；2)表征Ihog和Boi在轴突引导和HH转运中的新功能；3)研究Tutl在轴突引导中的作用。这项发现拨款建立在前三年为识别新型轴突引导分子而资助的研究的基础上。我们的创新研究项目为学生提供出色的概念和技术培训，我们的长期目标是在分子水平上解释大脑中神经回路在发育过程中构建和组装所依据的原理。

The ability of the brain to function properly relies upon patterned development of neurons and the controlled establishment of synaptic connections. The overall objective of our research program is to use the Drosophila model system to understand these processes at a molecular and cellular level. We are investigating how extrinsic signals influence the differentiation of neurons and the guidance of axons via three transmembrane proteins of the immunoglobulin superfamily (IgSF) known as Ihog, Boi and Tutl. In the previous 3-yr term of this Discovery Grant, students in the van Meyel lab have made exciting discoveries that implicate Ihog, Boi and Tutl as key regulators of neuronal differentiation and/or axon guidance. These IgSF proteins are conserved in other species including mammals, and they are comprised of ectodomains with Ig-like and fibronectin type III repeats, a transmembrane domain, and a cytoplasmic tail. We have found recently that Ihog and Boi are functionally redundant and essential for signaling via the Hedgehog (Hh) pathway. Hh is an important determinant of neuronal differentiation in the retina, spinal cord, brain, and many other cell types. We have also found that Tutl is important patterned growth and guidance of axons and dendrites, but the mechanism of action of Tutl remains completely mysterious. The specific objectives of this research program are to: 1) determine how Ihog and Boi participate in the Hedgehog signaling pathway, 2) characterize new functions for Ihog and Boi in axon guidance and Hh transport and 3) investigate the role of Tutl in axon guidance. This Discovery Grant builds on the foundation of research funded over the previous 3-yr period to identify novel axon guidance molecules. Our innovative research program provides excellent conceptual and technical training for students, where our long-term goal is to explain at a molecular level the principles upon which neural circuits in the brain are built and assembled during development.