Transcriptional Control of Motor Neuron Maturation

我们从多能干细胞中产生神经元的能力为研究神经元的组装带来了巨大的希望， 功能和功能障碍的神经系统在实验可及的设置。虽然有 干细胞分化为日益多样化的细胞的新方案的发展取得了巨大进展， 神经元的类型，干细胞衍生的神经元不能获得完全成熟的神经元身份。为了研究 成熟神经细胞的功能，并在更相关的背景下模拟成人发作的神经退行性疾病， 因此，最重要的是开发出一种方法，使神经细胞更接近于成人的神经细胞。 CNS。为了实现这一目标，我们将进行一个纵向研究的基因表达和染色质的变化， 小鼠脊髓中的初级运动神经元。我们将确定控制成熟基因表达的增强子 编程并开发用于将未成熟干细胞衍生的运动神经元重编程为成熟状态的方法。 这项工作将影响三个重要领域：1）它将首次提供基因表达的详细分析 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）它将产生一种新的有效的方法来重编程未成熟的干细胞 细胞来源的运动神经元到一个更成熟的状态，将作为一个更好的模型，成人发病 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.