Transcriptional Control of Motor Neuron Maturation

我们从多能干细胞产生神经元的能力为研究组装提供了巨大的希望， 在可实验的环境中，神经系统的功能和功能障碍。虽然已经有了一个 干细胞分化为越来越多样化的新方案的开发取得了巨大进展 对于不同类型的神经元，干细胞来源的神经元不能获得完全成熟的神经元身份。为了更好地研究 成熟神经细胞的功能，并在更相关的背景下模拟成人起病的神经退行性疾病， 最重要的是开发出与成人神经细胞更接近的方法。 中枢神经系统。为此，我们将进行一项基因表达和染色质变化的纵向研究 小鼠脊髓内的初级运动神经元。我们将确定控制成熟基因表达的增强子 为未成熟的干细胞来源的运动神经元重新编程到成熟状态的程序和开发方法。 这项工作将影响三个重要领域：1)它将提供第一个详细的基因表达分析 与体内运动神经元成熟相关的变化，2)它将定义新的转录调节因子 控制神经元的成熟；3)这将为未成熟干细胞的重新编程提供一种新的有效方法 细胞衍生的运动神经元进入更成熟的状态，这将成为成人发病的更好模型 神经退行性疾病，如肌萎缩侧索硬化症。

Our ability to produce neurons from pluripotent stem cells holds great promise for studying the assembly, function, and dysfunction of the nervous system in experimentally accessible settings. While there has been a dramatic advance in the development of new protocols for differentiation of stem cells into increasingly diverse types of neurons, stem cell-derived neurons fail to acquire a fully mature neuronal identity. In order to study the function of mature nerve cells and to model adult onset neurodegenerative disorders in a more relevant context, it is paramount to develop methodologies that yield nerve cells more closely resembling those found in the adult CNS. Towards this goal, we will perform a longitudinal study of gene expression and chromatin changes in primary motor neurons in the mouse spinal cord. We will identify enhancers that control mature gene expression programs and develop methods for reprograming immature stem cell-derived motor neurons to a mature state. This work will impact three important areas: 1) it will provide the first detailed analysis of gene expression changes associated with motor neuron maturation in vivo, 2) it will define new transcriptional regulators controlling neuronal maturation, and 3) it will yield a new effective method for reprogramming immature stem cell-derived motor neurons to a more mature state that will serve as a better model for adult-onset neurodegenerative diseases, such as amyotrophic lateral sclerosis.