Determining the Transcription Factor Code that Specifies CiA Interneurons

目前，我们治疗神经系统疾病或脊髓损伤患者的能力受到对中枢神经系统如何发育和功能的有限了解的限制。特别是，我们对不同类型的神经细胞(神经元)是如何形成的知之甚少。在这项研究拨款中，我们的目标是确定哪些基因参与了斑马鱼胚胎中特定数量的脊髓神经元，即中央情报局中间神经元的形成。脊髓是背部脊柱内神经系统的一部分，负责控制身体运动，并从身体和四肢接收关于疼痛、触摸和热量的信息。这就是为什么脊髓受损的人经常瘫痪的原因。为了让脊髓的神经元回路发挥作用，特定的神经元需要在特定的位置发育，并相互建立适当的连接。对于这些过程是如何监管的，我们仍然知之甚少。令人兴奋的是，我们现在可以利用斑马鱼胚胎的细胞生物学和遗传学来识别活胚胎中的特定神经元，并确定它们的位置、细胞形状、神经元连接和功能是如何指定的。我们已经确定了几个调控基因，我们认为这些基因对于指导CIA中间神经元获得其特定特征(例如神经细胞的形状、它与哪些其他神经细胞通信以及它用来通信的化学物质)是重要的。这些基因编码被称为转录因子的调节蛋白，这些转录因子负责开启和关闭其他基因。在这个项目中，我们将测试这些转录因子在制造CIA中间神经元方面的单独和联合功能。CIA中间神经元的组成和功能与哺乳动物(V1细胞)中特定群体的中间神经元非常相似，因此我们的发现也应该与人类相关。这项研究很重要，因为我们对不同神经元是如何形成的了解越多，我们就越有可能开发出治疗神经疾病和/或脊髓损伤的方法。例如，一旦我们知道哪些基因指定了特定的神经元，我们就可以使用这些信息来指示干细胞生长到这些神经元。

Our ability to treat people with neurological disorders or spinal cord injuries is currently constrained by our limited understanding of how the central nervous system develops and functions. In particular, we know very little about how different types of nerve cells (neurons) are made. In this research grant we aim to determine which genes are involved in making a specific population of spinal cord neurons, called CiA interneurons, in zebrafish embryos. The spinal cord is the part of the nervous system inside the vertebral column in the back and it is responsible for controlling body movements and for receiving information about pain, touch and heat from the body and limbs. This is why people with damaged spinal cords are often paralysed. For the neuronal circuitry of the spinal cord to function, specific neurons need to develop in particular positions and make appropriate connections with each other. We still know very little about how these processes are regulated. Excitingly, we can now exploit the cell biology and genetics of zebrafish embryos to identify specific neurons in live embryos and determine how their positions, cell shapes, neuronal connections and functions are specified. We have identified several regulatory genes that we think are important for instructing CiA interneurons to acquire their particular characteristics (e.g. shape of the nerve cell, what other nerve cells it communicates with and the chemicals that it uses to communicate). These genes encode for regulatory proteins called transcription factors which are responsible for turning other genes on and off. In this project, we will test the individual and combined functions of these transcription factors in making CiA interneurons. CiA interneurons are made and function in very similar ways to a specific population of interneurons in mammals (V1 cells), so our findings should also be relevant to humans. This research is important because the more we learn about how different neurons are made, the more likely we are to be able to develop treatments for neurological diseases and/or spinal cord injuries. For example, once we know which genes specify particular neurons we can use this information to instruct stem cells to grow into those neurons.