Control of Neuronal Circuit Assembly by Gtpase Regulators

One of the most remarkable features of the central nervous system is the exquisite specificity of its synaptic connections, which is crucial for the functioning of neuronal circuits. Thus, understanding the cellular and molecular mechanisms leading to the precise assembly of neuronal circuits is a major focus of developmental neurobiology. The structural organization and specific connectivity of neuronal circuits arises from a series of morphological transformations: neuronal differentiation, migration, axonal guidance, axonal and dendritic arbor growth and, eventually, synapse formation. Changes in neuronal morphology are driven by cell intrinsic programs and by instructive signals from the environment, which are transduced by transmembrane receptors on the neuronal cell surface. Intracellularly, cytoskeletal rearrangements orchestrate the dynamic modification of neuronal morphology. A central question is how the activation of a neuronal cell surface receptor triggers the intracellular cytoskeletal rearrangements that mediate morphological transformations. A group of proteins linked to the regulation of cytoskeletal dynamics are the small GTPases of the Rho family. Small RhoGTPases are regulated by GTPase exchange factors (GEF) and GTPase activating proteins (GAP), which can switch GTPases into "on or off" states, respectively. It is thought that GEFs and GAPs function as intracellular mediators between transmembrane receptors and RhoGTPases to regulate cytoskeletal rearrangements. During my dissertation I identified the GAP α2-chimaerin as an essential downstream effector of the axon guidance receptor EphA4, in the assembly of neuronal locomotor circuits in the mouse. Furthermore, I identified two novel neuronal GAPs, mSYD-1A and mSYD-1B, which interact with components of the presynaptic active zone and which may contribute to presynaptic assembly downstream of synaptic cell surface receptors.