Signaling mechanisms underlying axon growth

Date of Award




Degree Name

Doctor of Philosophy (Ph.D.)


Molecular and Cellular Pharmacology

First Committee Member

John L. Bixby - Committee Chair


In the developing nervous system, the regulation of axonal growth and guidance is the responsibility of many different proteins. However, regardless of the number of different growth-promoting proteins and the pathways that they may employ, a common end of positively regulating axon growth and guidance is achieved. This implies that signals generated by growth-promoting proteins may converge at key points, utilizing the same or similar signaling cascades, to transduce appropriate growth-promoting information. To begin to define these points of convergence for growth-promoting signal transduction, we examined whether the ERK (E&barbelow;xtracellular Signal-R&barbelow;egulated K&barbelow;inase)/MAP (M&barbelow;itogen-A&barbelow;ctivated P&barbelow;rotein) kinase transduction pathway could support signaling initiated by several distinct classes of growth-promoting molecules. Increased ERK activity in embryonic day 6 (E6) retinal neurons was measured in response to three distinct growth-promoting molecules: basic fibroblast growth factor (bFGF), laminin (LN), and N-cadherin. Substrate activation, by LN and N-cadherin, caused a redistribution of ERK to the plasma membrane in these neurons. Inhibition of substrate-induced ERK activity resulted in an inhibition of the substrate-induced redistribution of ERK to the plasma membrane, as well. The enhanced neurite outgrowth observed in retinal neurons stimulated with bFGF, LN, and N-cadherin is also strongly dependent on ERK activity. These data suggest that ERK may be a point at which distinct signaling pathways converge to regulate axonal growth.Some mechanisms of signal transduction have been shown to involve the aggregation of cell surface and intracellular signaling molecules into large multi-molecular signaling complexes. The tetraspanin superfamily of transmembrane proteins are commonly found in multi-molecular complexes. Many of the proteins found in association with tetraspanins are integrin subunits. Integrins are receptors for extracellular matrix proteins, such as LN, and mediate their growth-promoting abilities. Interestingly, a vertebrate tetraspanin has been implicated in integrin-dependent axonal growth. To further define the members of the tetraspanin superfamily expressed in the nervous system, a degenerate PCR screen of embryonic day 6 (E6) chicken spinal cord was performed. Spinal motorneurons are growing towards and synapsing with their targets at this time in development, and are therefore actively using the very types of transduction mechanisms responsible for axon growth and guidance. A novel tetraspanin, named neurospanin, was identified from the PCR screen and cloned, along with the chick homologues of mammalian tetraspanins, NAG-2 and CD9. Analysis of the developmental and tissue expression profiles of these three neuronally expressed tetraspanins suggests that these proteins may play important roles at different stages of neuronal development. The expression pattern of neurospanin, in particular, indicates that this tetraspanin may be involved in early developmental processes, such as axonal growth and/or guidance mechanisms.


Biology, Neuroscience; Biology, Cell

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