Identification and functional characterization of molecular targets of the Sox2 transcription factor in human inherited brain disease: an approach through Sox2 conditional knockout in mouse

Mutations in the Sox2 gene cause a genetic disease comprising various brain defects, affecting eyes and hippocampus(a region essential for memory), that originate during brain development. The product of the Sox2 gene is a protein that controls the activity of other genes, a "transcription factor". Recently, it was found that some genes that, when mutated, cause genetic disease, are controlled by Sox2. To understand how Sox2 mutations cause disease, we thus wish to define functionally important genes controlled by Sox2. To do this, we obtained mice in which it is possible to eliminate (mutate) the Sox2 gene in a controlled way, and study the consequences of Sox2 loss on the activity of genes in the developing nervous system. In these mice, Sox2 mutation during development produces defects similar to those observed in Sox2-mutant patients, in particular a defective hippocampus and other abnormalities. We found that, in our mice, Sox2 loss caused loss of activity of a gene responsible for the production of a signalling molecule, SHH, essential to deliver growth signals to the developing hippocampus and to structures at the basis of the brain. We thus administered the mice a drug, that mimicks SHH, and correct brain and hippocampal growth recovered, in part. We now wish to identify further genes regulated by Sox2, by looking initially for genes that are less (or more) active following Sox2 loss, and then identifying, among them, those directly controlled by Sox2. We will study the mechanisms by which Sox2 directs their activity to specific regions of the developing brain. Finally, we will assess if reactivation of these genes, in the absence of Sox2, can ameliorate aspects of the disease in mice. The identification of genes downstream to Sox2 whose de-regulated activity causes specific aspects of the disease could pave the way for novel therapy hypotheses, aiming at "giving back" the products of these specific genes, or drugs substituting for their missing activity.