Researchers will use cellular imaging in the fruit fly and mice to gain a better understanding of the signaling processes that regulate nervous system wiring and how such signaling may go awry in brain diseases such as Amyotrophic Lateral Sclerosis (ALS).
Signaling pathways regulate the differentiation, growth, and function of all cells. In the nervous system, there are several types of electrochemical signals (called neurotransmitters). The signals pass from the cell body, along its axon (communication cable), through a synapse that connects to a neighboring cell’s dendrite, and from there the signal travels up to the neighboring cell’s body. Cells using the same type of neurotransmitter communicate with one another this way. Scientists do not yet know, however, how the correct formation, assembly and maturation of specific synapses occur to facilitate this communication, especially when the signals need to travel long distances along axons to move from one cell to another. Moreover, how do the synaptic defects that occur in conditions, such as ALS, occur?
Recent research indicates that cytokines, proteins that affect the activities of other cells, play an important role in the normal development, and disease-related dysfunction, of synapses. Specifically, the researchers hypothesize, a family of cytokines, called Transforming Growth Factor Beta (TGF-β), regulates the development and functioning of neural cell synapses that use the transmitter glutamate to communicate. These glutamate-transmitting cells are destroyed in ALS. The investigators will use the fruit fly as a genetic screening tool to identify TGF-β genes involved in formation of synapses that use glutamate. They will then study, in transgenic mice, the relevance of these genetic factors to the development of synapses that transmit glutamate signals from brain stem cells to cerebral cortex cells.
Significance: Information on how TGF-β signaling directs nervous system wiring of glutamate-transmitting cells may help to further our understanding of brain development and of how alterations in these signaling pathways may contribute to the death of glutamate-transmitting cells in ALS and other devastating brain diseases.