Tuberous Sclerosis Complex (TSC) is a common genetic disorder affecting many different organs including skin, brain, liver, kidney, retina, and lung. TSC is characterized by slow-growing benign tumors occasionally with malignant tumors. The majority of patients develop symptoms caused by the nervous system abnormality, such as seizures, mental retardation, attention-deficit disorders, and autism. While it is important to understand the molecular mechanism of the effect of TSC disease on the nervous system, not much is known due to a lack of good animal model system to study this aspect of TSC disease. We propose to use fruit fly, Drosophila melanogaster, to study the functions of TSC genes in the nervous system.

Drosophila provides an excellent model system to study functions of human disease genes. Most of the genome structures of Drosophila and human have been determined recently and revealed many genes in common between human and fruit fly. The Drosophila system has already contributed considerably to understanding functions of human disease genes. From the studies of human TSC patients, two genes, TSC1 and TSC2, have been identified whose mutations are responsible for TSC disease. Mutations in either TSC1 gene or TSC2 gene seem to produce exactly the same disease symptoms. We have discovered that the fruit fly, Drosophila melanogaster, also has TSC1 and TSC2 genes (dTSC1 and dTSC2 genes). We have also shown that mutations in either dTSC1 or dTSC2 can cause abnormal cell enlargement and excess cell growth. In this study, we propose to study the effect of mutations in TSC genes on the growth and connection of neurons. Individual nerve cells have characteristic patterns of connections with other nerve or non-nerve cells. We will label the mutant cells, visualize the projections of nervous cells, and compare the structures of mutant nervous cells with those of normal nervous cells. We will also compare projections of TSC mutant nervous cells with other known mutations to understand molecular mechanism of TSC functions.

Since it is very difficult to visualize the projections of individual nervous cells in human or mouse, Drosophila gives us a unique system to study the structure of individual nerve cells. Nervous cells have many contacts with other nervous and non-nervous cells, and the patterns of these contacts determine the function of brains. This project takes an innovative approach to combine powerful genetics using Drosophila and a new technique to label single nervous cells inside bodies. The better understanding of the effect of TSC mutations on nervous cells will be important for developing effective treatments for human TSC patients, especially symptoms related to brain functions.