Regulation of retinal neurite growth by alterations in MAPK/ERK kinase (MEK) activity

Activation of the extracellular-signal regulated kinase (ERK) cascade may be involved in the promotion of neurite outgrowth by a variety of stimuli. For example, we have previously shown that laminin (LN) and N-cadherin activate ERK2 in chick retinal neurons, and that pharmacological inhibition of MAPK/ERK kinase (MEK), the major upstream ERK2 activator, severely impairs neurite growth induced by these proteins. We have therefore hypothesized that ERK activation through MEK is required for optimal induction of neurite growth by these proteins. Here we show that expression of mutant MEK in transfected retinal neurons alters neuronal responses to LN in a manner consistent with this hypothesis. Neurons expressing a constitutively active MEK construct extended longer neurites on LN than controls, while neurons transfected with a dominant negative construct extended shorter neurites. Further, experiments in which transfected neurons were replated onto polylysine substrates suggest that activation of MEK is sufficient for neurite promotion on a non-inducing substrate, and neurons replated onto LN confirm the pharmacological data that inhibition of MEK activation inhibits LN-induced neurite growth. We conclude that ERK activation plays a direct role in the promotion of neurite outgrowth from retinal neurons by LN.