Spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders that cause infant mortality. SMA is caused by loss of the Survival of Motor Neuron (SMN) protein, resulting in motor neuron (MN) degeneration in the spinal cord. Although SMN protein plays diverse roles in RNA metabolism and is expressed in all cells, it is unclear why a deficiency in SMN only causes MN degeneration. Since patient samples are rarely available, most knowledge in SMA is gained from animal model studies. While these studies have provided important insights of the cause and mechanism of SMA, they are limited by complicated genetic manipulation. Results from different models are also not always consistent. These problems can be addressed using induced pluripotent stem cells (iPSCs) derived from patient’s fibroblasts. These cells, due to their self-renewal capacity and their ability to differentiate into neuronal cells, can in theory provide an unlimited supply of the affected MNs for SMA study. We propose to examine cellular and functional deficits in MNs derived from these SMA iPS cells in Aim 1. To increase the yield of MN production, we have tested new strategies to differentiate SMA iPSCs into MNs. The improvement makes it feasible to isolate more pure populations of MNs for the study of SMA pathogenesis in vitro. The availability of these iPSC lines also provides an opportunity to explore the mechanisms of selective MN degeneration in SMA. Dysregulation of some cellular genes has been implicated in SMA pathogenesis. We continue to study the role of one particular cellular gene whose expression is reduced in SMA (Aim 2). We are taking approaches to reveal how SMN deficiency causes this change in gene expression. We are also taking a genomic approach to reveal all the affected genes and the signaling pathways in SMA MNs and understand how a deficit in these genes leads to selective MN degeneration (Aim 3). Our study should provide valuable insights in the understanding of SMA pathogenesis and aid in exploring new molecular targets for drug intervention.