Tuberous Sclerosis is one of the most common neurocutaneous disorders, afflicting 1 in 6,000 live births. Children typically present with autism, mental retardation, epilepsy, and psychiatric disorders. Tuberous sclerosis is caused by mutations in two genes that form a protein complex (TSC), Tsc1 and Tsc2.
Work in simple model organisms such as Drosophila has revealed that TSC has a conserved function in growth control. Subsequent work in mammalian systems has demonstrated that TSC acts through the same pathway in all organisms, but it is unclear how loss of TSC leads to the neurological defects seen in patients.
Through genetic screens in Drosophila, we recently discovered that TSC has an important role in controlling when cells adopted a neuronal fate. If a cell chooses a neuronal fate at the wrong time, severe consequences in the ability of that cell to make the proper axonal connections may result; this may explain some of the neurological problems observed in TSC patients.
To understand how TSC regulates neural fate decisions we need to find genes that function downstream of TSC in controlling neuronal fate. We will determine the mechanisms in Drosophila, where the studies needed to make mechanistic insights are well established, and the simpler genome allows more rapid progress than is possible in mammalian systems.
We will use new high-throughput tools to rapidly screen the entire Drosophila genome to identify genes that function in the TSC pathway of neuronal differentiation. Since TSC has been shown to regulate the abundance of proteins involved in growth control, we will test if the abundance of pro-neural proteins is similarly regulated. In addition, we will examine transcriptional targets of TSC, to understand how TSC regulates their expression. Once we understand how the loss of TSC leads to premature cell fate decisions in Drosophila, we will be able to extend these findings to man and establish a basis for developing rational treatments for the neural defects associated with tuberous sclerosis.