The overwhelming majority of human genes undergo extensive alternative splicing, but save for several dozens of these regulated splicing events, it is not known which proteins are responsible for controlling these key splicing decisions. Furthermore, mutations in several of these proteins, known as splicing factors, have recently been shown to be causative of neurodegeneration. In this proposal we aim to understand the importance of splicing factor regulation of alternative splicing in controlling pluripotency, fate decision towards the neural lineage and neuronal survival. In our recent publication in Cell Reports, Huelga et al demonstrated that the ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs) commonly cooperate and antagonize one another to regulate alternative splicing in a somatic human cell-line. In year one of this grant, we have interrogated several key members of these hnRNP proteins in human neural progenitor and differentiated neurons from embryonic stem cells and induced pluripotent stem cells.