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 have been elucidated, 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. First, 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. Second, the proposed studies will elucidate the mechanism(s) by which ARX and ARX-associated network influence cortical progenitor proliferation and patterning. Third, the proposed studies will delineate the role of ARX and ARX-associated network in GE progenitor cell development. These studies are expected to provide a greater understanding of how ARX functions in normal and abnormal brain development, and will contribute to our understanding of the pathogenesis of such common disorders in children as intellectual disabilities, epilepsy, autism, and structural anomalies of the brain.
The studies proposed in this application are aimed to understand the roles of one transcription factor, ARX, and its associated network, in neocortical development. Neurodevelopmental disabilities affect over 15% of children in the US and extract a significant financial burden on the US health care dollar, an estimated $51.2 billion (in 2003 dollars). Unfortunately, in most cases, the underlying pathogenesis is poorly understood. Ultimately, we expect our proposed studies will lead to improvements in our understanding of neurodevelopmental disabilities as well as in the diagnosis, treatment, and prevention of these and other related disorders.
