Understanding the Function of Tuberous Sclerosis Complex Genes in Neural Development: Roles in Synapse Assembly and Axon Guidance

Project: Research project

Project Details



Tuberous sclerosis complex was first described in the early 1880's by Bourneville as a disorder characterized by mental retardation, intractable seizures, and "tubereuse," the white, hard benign tumors found in multiple tissues. This earliest report serves to point out the severe neurological and behavioral consequences of this genetic disorder. While mental retardation and seizures are no longer considered essential diagnostic features for tuberous sclerosis complex on account of their lack of specificity, it is important to bear in mind that many children with tuberous sclerosis complex have structural brain abnormalities and approximately 90% have seizures. Behavioral disorders are also prevalent in tuberous sclerosis complex-affected children. Autism spectrum disorder (also known as pervasive developmental delay) is reported in approximately 50% of children with a tuberous sclerosis complex diagnosis, and rates of attention-deficit-hyperactivity are similarly high.

We now know that tuberous sclerosis complex is the result of mutations in either one of two genes, TSC1 or TSC2. TSC1/2 code for distinct proteins that bind to one another in cells, and together regulate an essential signaling system that controls cell growth. While it is now clear that TSC1 and TSC2 cooperate to control cell growth, how they affect the function of the nervous system is not understood.

The scientific objective of our research is to determine how disruption of tuberous sclerosis gene function affects development of the nervous system, as a means of understanding the neurological and behavioral problems associated with this disorder.

Preliminary work we have done indicates that loss of TSC gene function disrupts two fundamental processes required for development of the nervous system, how cells in the brain connect with one another, and how they communicate at specialized junctions called synapses. We also have evidence that these abnormalities in nervous system development steps do not involve the same steps that produce defects in cell division and growth, but likely affect how cells organize their internal "skeleton." Most importantly, these defects are not corrected by the class of drugs known to block abnormal cell growth when TSC gene function is lost. Our work therefore shows that TSC gene activity influences many cellular functions, and those signaling systems that affect cell growth may be distinct from those that produce neurological problems.

A main goal of our work is to identify potential molecular targets for reversing or preventing the defects in nervous system development that accompany loss of TSC gene function.

Our work takes advantage of the conservation of TSC genes and their functions between many different organisms. A great deal of what we understand about TSC function today derives from the simple model system the fruitfly, Drosophila. Virtually all of the genes involved in the signaling systems affected by TSC are represented in this simple model organism. This is critical, because it means that studies that identify how disruption of TSC function affects Drosophila, provide important clues that can often be directly translated to humans. Most of the work to date in understanding TSC function, both in humans and model organisms such as the mouse and Drosophila, has focused on the disruptions of cellular growth. Our goal is to use this model to understand the basic defects in nervous system development that occur when TSC function is compromised. Two critical aspects of nervous system development that can be readily studied in this simple system are (1) how neurons connect to one another, and (2) how the specialized connections between neurons, or neurons and muscle, called synapses, form.

Our studies will identify the molecules that mediate the changes in neural development that accompany loss of TSC gene function in Drosophila, and hence provide direction for research in vertebrate systems that could lead to medications designed to prevent or reverse the neurological and behavioral deficits in children with tuberous sclerosis complex.

Effective start/end date1/1/0612/31/06


  • U.S. Department of Defense: $560,202.00


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