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.
We will study mechanisms that control maturation of spinal cord motor neurons. Understanding this process will enable us to accelerate maturation of stem cell-derived neurons, leading to more accurate models for adult onset degenerative diseases, such as ALS.