Cell type specification in developing CNS: functional analysis of Sox14

中枢神经系统(CNS)是人体最复杂的器官。中枢神经系统中的绝大多数神经细胞被归类为“中间神经元”。这些细胞在中枢神经系统内传递感觉信息和运动指令。中间神经元功能的异常很可能是一些(如果不是许多)人类神经系统疾病的根本原因。然而，对于中间神经元的精确解剖和功能，哪些基因控制着它们的发育，以及这些功能是如何在成人中保持的，人们知之甚少。这在很大程度上是由于缺乏有效和可靠的方法来识别和研究中间神经元。我们之前已经发现，一种名为Sox14的基因在胚胎大脑和脊髓中的不同中间神经元组中活跃。Sox14是Sox基因家族的成员之一，其中许多基因充当控制细胞和组织发育的遗传开关。我们发现，Sox14在整个进化过程中都被保存得非常好，并且在许多动物物种的类似中间神经元群中都很活跃。这些研究让我们假设，Sox14控制着某些中间神经元产生的关键分子步骤，这些中间神经元可能参与反射、运动或运动协调。在这个项目中，我们将研究Sox14在中间神经元发育中的作用以及该基因激活的中间神经元的功能。我们将通过将现代分子和基因技术与生理学方法相结合来做到这一点。该项目将揭示中枢神经系统发育中的关键分子步骤，并确定特定组中间神经元的功能。为此，我们将产生小鼠品系，在这些品系中，特定的一组中间神经元被遗传标记，并可以在发育期间进行操纵。我们设想，这些具有“改良脑回路”的小鼠将成为未来研究选定的中间神经元类型及其功能的独特资源。

The central nervous system (CNS) is the most complex organ in the body. The vast majority of nerve cells in the CNS are classified as 'interneurons'. These cells relay sensory information and motor commands within the CNS. Abnormal functioning of interneurons is likely to be the underlying cause of some, if not many, human nervous system diseases. However, very little is known of the precise anatomy and function of interneurons, which genes control their development, and how these functions are maintained in the adult. This has been largely due to a lack of efficient and reliable methods to identify and study interneurons. We have previously discovered that a gene termed Sox14 is active in distinct interneuron groups in the embryonic brain and spinal cord. Sox14 is a member of the Sox gene family, many of which act as genetic switches to control cell and tissue development. We found that Sox14 has been extremely well conserved throughout evolution and is active in similar interneuron groups in a number of animal species. These studies led us to hypothesise that Sox14 controls a critical molecular step in the generation of certain interneurons that may be involved in reflexes, locomotion or motor coordination. In this project, we will investigate both the role of Sox14 in interneuron development and the functions of interneurons in which this gene is active. We will do so by combining modern molecular and genetic techniques with physiological approaches. This project will reveal critical molecular steps in CNS development and determine the functions of a specific group of interneurons. To this end, we will generate mouse strains in which a specific group of interneurons are genetically marked and can be manipulated during development. We envisage that these mice with 'modified brain circuits' will become unique resources for future investigations of selected interneuron types and their functions.