06-P016 The Shh cis-regulatory element, ZRS, functions to specify spatial information

thesis, absorption or flow of the Cerebral Spinal Fluid (CSF) and is a common developmental disability in humans. Although CH has a significant genetic component in mice and humans, it is poorly understood at the molecular level. The Subcommissural Organ (SCO), a gland residing at the dorsal opening of the Sylvian aqueduct, has been implicated in CSF flow maintenance. We have established BAC transgenic mouse lines overexpressing the transcriptional activator Sry-related HMG box 3 (Sox3). Sox3 is highly expressed in most progenitor cells of the embryonic central nervous system (CNS) including the precursors of the SCO. 20% of single transgenic adult mice and 99% of double transgenic adult mice exhibit overt CH (dome shaped cranium). Classical hallmarks of CH including expanded lateral ventricles and thinning of the cerebral cortex were evident in transgenic brains from E18.5. Expression of the transgene was high in the SCO during development (E11.5– E18.5) and adulthood. Importantly, severe SCO hypoplasia is apparent from E15.5 in double transgenic embryos. Intriguingly, increased proliferation was observed in E12.5 Sox3 double transgenic SCO primordia by BrdU-incorperation. These data suggest that defective SCO development is responsible for hydrocephalus in the Sox3 transgenic model. Detailed analysis of the genes regulated by Sox3 is being undertaken to understand the role of Sox3 in SCO development. Our mouse model allows the identification of CH candidate genes and provides improved understanding of the underlying genetic basis for CH in humans.