Signals regulating neurite growth

Date of Award




Degree Name

Doctor of Philosophy (Ph.D.)



First Committee Member

John L. Bixby - Committee Chair


Correct pathfinding of axons to reach the right target requires molecular and cellular signals. Different molecules are required, which often converge on similar targets. One target is the extracellular-signal regulated kinase (ERK), involved in the promotion of neurite outgrowth by a variety of stimuli. Laminin (LN) can activate ERK in retinal neurons and neurite outgrowth induced by LN is impaired when MAPK/ERK kinase (MEK), an upstream ERK activator, is inhibited pharmacologically. We have hypothesized that ERK activation through MEK is required for optimal induction of neurite growth by LN. Neurons expressing a constitutively active MEK construct extend longer neurites on LN than controls, while neurons transfected with a dominant negative MEK construct extend shorter neurites. Activation of MEK is sufficient for neurite promotion on neutral substrates and neurons pharmacological inhibition of MEK activation inhibits LN-induced neurite growth. Therefore, ERK activation plays a direct role in the promotion of neurite outgrowth from retinal neurons by LN.During neuromuscular development, after motor axons reach their muscle targets, differentiation of both pre- and postsynaptic elements occurs. Presynaptic differentiation requires motor neuron "stop-signals." Motor neuron stop-signals, present on the myotube surface are thought to induce adhesion of motor axons to the myotube, inhibition of motor axon growth and the clustering of synaptic vesicles at sites of axon-myotube contact. Both agrin and its muscle receptor, MuSK, are required for motor axon stop-signal function. To test whether MUSK complexes act directly as stop-signals in the absence of myotube signaling, ciliary ganglion (CG) neurons were co-cultured with human embryonic kidney (HEK) cells, or with HEK cells expressing cell-surface MuSK. MuSK expression was neurite-inhibitory for CG neurons; this effect is not seen with other projection-type neurons. The inhibition of neurite growth was more pronounced when HEK cells co-express the CT glycosyltransferase. Neurite inhibition on MuSK-transfected cells could be partially reversed by treatment with either an antibody to MuSK or an antibody to agrin. Our results suggest that an agrin/MuSK complex forms at least one motor neuron stop-signal, and are consistent with the involvement of the CT antigen in the interaction of agrin and MuSK.


Biology, Molecular; Biology, Neuroscience

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