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

Activation of the extracellular-signal regulated kinase (ERK) cascade may b e involved in the promotion of neurite outgrowth by a variety of stimuli. F or example, we have previously shown that laminin (LN) and N-cadherin activ ate 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 th at ERK activation through MEK is required for optimal induction of neurite growth by these proteins. Here we show that expression of mutant MEK in tra nsfected retinal neurons alters neuronal responses to LN in a manner consis tent with this hypothesis. Neurons expressing a constitutively active MEK c onstruct extended longer neurites on LN than controls, while neurons transf ected with a dominant negative construct extended-shorter neurites. Further , experiments in which transfected neurons were replated onto polylysine su bstrates suggest that activation of MEK is sufficient for neurite promotion on a non-inducing substrate, and neurons replated onto LN confirm the phar macological data that inhibition of MEK activation inhibits LN-induced neur ite growth. We conclude that ERK activation plays a direct role in the prom otion of neurite outgrowth from retinal neurons by LN. (C) 2000 Published b y Elsevier Science B.V. All rights reserved.