Arx Associated Transcriptional Networks In Neocortical Development

Neurodevelopmental disorders (intellectual disability, epilepsy, autism, attention deficit, etc.) are diagnosed in 1 in 6 children in the US according to the report from the Center for Disease Control and Prevention. Despite this high frequency, the molecular and cellular basis for only a few disorders has been elucidated, while the basis of most remains unknown. Interestingly, patients with mutations in ARX exhibit nearly all of these features. However, the developmental mechanism by which ARX mutations result in this wide spectrum of problems is incompletely understood. Our prior work has demonstrated that ARX is expressed in two different neural progenitor populations during forebrain development and that it plays distinct roles in each population by regulating different subsets of genes. Furthermore, we have shown that the loss of Arx from each progenitor population accounts for specific components of the mouse and human phenotypes. In this proposal, building on our data from the past ten years, we seek to understand how ARX regulates different subset of genes in different progenitor populations. The proposed studies will focus on identification of ARX-interacting transcription factors (or co-factors) and their down-stream target genes co-regulated by ARX in each cell population. The combination of proteomics and genomics approach as well as systematic network analysis will identify the key target genes predicted to play crucial roles in each progenitor specific, ARX-mediated, cellular functions that we previously defined. Finally, we will validate these predicted genes with in vivo functional analysis.