Role of DSCAM in the development of motor circuits

运动控制是大脑和脊髓相互作用的结果。大脑启动、选择和计划适当的运动程序以匹配环境限制，而脊髓则将这种下行命令翻译成运动动作。对运动功能至关重要的是大脑和脊髓中神经元网络的形成，这高度依赖于信号通路。这些信号分子中的一些被认为引导生长的轴突到达它们合适的目标，而另一些则有助于细胞在中枢神经系统中的定位。利用小鼠遗传学，现在可以通过小鼠的基因缺失或过度表达来改变基因表达，从而使我们能够拓宽和深化对运动回路发展至关重要的信号分子的理解。我的研究计划集中在其中一些信号通路上，例如DSCAM(一种与唐氏综合症有关的细胞黏附分子)。最近，我们利用缺乏DSCAM的突变小鼠，证明了DSCAM对运动控制和姿势调整是重要的，它有助于脊髓运动和感觉运动回路的正常发育，以及运动皮质的建立。我在当前项目中的短期目标是确定和描述DSCAM如何有助于形成对运动控制和运动至关重要的皮质、脊髓和感觉回路。使用CRE-LOX技术，我们将通过在特定神经元群体中过度表达或突变来操纵DSCAM的表达，以研究DSCAM如何在解剖学、生理学和功能上对小鼠脊柱上、脊髓和感觉回路的建立做出贡献。我们将致力于以下目标：目的1：研究DSCAM在运动皮质发育中的作用。目的2：鉴定和表征DSCAM在脊髓运动回路中的作用。目的3：评价DSCAM在建立脊髓感觉运动回路中的作用。随着为期5年的研究的完成，我们将更好地了解皮质、脊髓和感觉DSCAM的作用及其在运动控制和运动中的功能贡献。

Motor control results from the interplay between the brain and the spinal cord. The brain initiates, selects, and plans the appropriate motor program to match environmental constraints, while the spinal cord translates this descending command into motor actions. Critical to motor functions is the formation of neuronal networks in the brain and spinal cord, which depends highly on signaling pathways. Some of these signaling molecules are thought to guide growing axons to their proper targets, while others contribute to the cell positioning across the central nervous system. Using mouse genetics, it is now possible to alter gene expression by genetic deletion or overexpression in the mouse, thus allowing us to broaden and deepen our understanding of signaling molecules crucial to the development of motor circuits. My research program focuses on some of these signaling pathways, such as DSCAM (a cell adherence molecule associated to Down Syndrome). Recently, using mutant mice lacking DSCAM, we have shown that DSCAM is important to locomotor control and postural adjustments, it contributes to the normal development of the spinal locomotor and sensorimotor circuits, as well as the establishment of the motor cortex. My short-term objectives in the current program are to identify and characterize how DSCAM contributes to the formation of cortical, spinal, and sensory circuits important to motor control and locomotion. Using the CRE-LOX technology, we will manipulate DSCAM expression by overexpression or mutation in specific neuronal populations in order to investigate how DSCAM contributes anatomically, physiologically, and functionally to the establishment of supraspinal, spinal, and sensory circuits in the mouse. We will address the following aims:Aim 1: To study the contribution of DSCAM in the development of the motor cortex.Aim 2: To identify and characterize the role of DSCAM in the spinal locomotor circuit.Aim 3: To evaluate the role of DSCAM in the establishment of the spinal sensorimotor circuit.By the completion of the 5-year term of this research, we will have a better understanding of the role of cortical, spinal and sensory DSCAM, and their functional contribution to motor control and locomotion.