The role of ectodomain shedding in neurodevelopment

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During development cells in the nervous system wire together to form connections that regulate a multitude of simple and complex behaviors including sensory processing, motor control and cognition. Proper wiring requires nerve cells or neurons to extend processes through a complex environment to correct targets and to establish stable connections with other neurons are target tissues through contacts called synapses. Mutations in proteins required for synapse formation have been linked to neurodevelopmental disorders such as autism spectrum disorders. Further, normal remodeling of synapses is fundamental to our ability to learn and remember. Neurons express a host of receptor molecules on their cell surface that permit them to respond to environmental cues to form, stabilize and remodel synaptic connection. The ability of the cell to change its response to the extracellular environment is influenced by the ability of cells to shed cell surface proteins. Shedding of cell surface molecules can desensitize neurons to their environment and can also release bioactive fragments into the neuronal environment. Protein shedding is controlled by a family of proteins calls metalloproteinases that can desensitize neurons to cues in the environment by rapidly remodeling the repertoire of surface proteins. In this way neurons can dynamically regulate their response to the environment in space and time. We are studying the important roles that metalloproteinases play in spatial and temporal regulation of synapse formation. These studies will shed light on the fundamental science underlying synapse formation and remodeling, key processes underlying proper neuronal development and memory formation.