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Abstract
The formation and directional guidance of neurites involves dynamic regulation of Rho family GTPases. Rac and Cdc42 promote neurite outgrowth, whereas Rho activation causes neurite retraction. Here we describe a role for collapsin response mediator protein (Crmp-2), a neuronal protein implicated in axonal outgrowth and a component of the semaphorin 3A pathway, in switching GTPase signaling when expressed in combination with either dominant active Rac or Rho. In neuroblastoma N1E-115 cells, co-expression of Crmp-2 with dominant active RhoA V14 induced Rac morphology, cell spreading and ruffling (and the formation of neurites). Conversely, co-expression of Crmp-2 with dominant active Rac1 V12 inhibited Rac morphology, and in cells already expressing Rac1 V12, Crmp-2 caused localized peripheral collapse, involving Rho (and Cdc42) activation. Rho kinase was a pivotal regulator of Crmp-2; Crmp-2 phosphorylation was required for Crmp-2/Rac1 V12 inhibition, but not Crmp-2/RhoA V14 induction, of Rac morphology. Thus Crmp-2, regulated by Rho kinase, promotes outgrowth and collapse in response to active Rho and Rac, respectively, reversing their usual morphological effects and providing a mechanism for dynamic modulation of growth cone guidance.
Highlights
(Sema 3A) induces growth cone collapse in chick dorsal root ganglia (DRG) neurones, a response mediated by Rac 1 [8] acting through its effectors [9]
Collapsin response mediator protein-2 (Crmp-2), which is expressed in post-mitotic neurones [11], is implicated in the Sema 3A response [12] and is one of a family of proteins related to the Caenorhabditis elegans Unc 33 gene involved in axonal outgrowth [13]
We have found that expression of Crmp-2 in neuroblastoma N1E-115 cells can alter Rho-GTPase-driven morphology
Summary
(Sema 3A) induces growth cone collapse in chick dorsal root ganglia (DRG) neurones, a response mediated by Rac 1 [8] acting through its effectors [9]. We describe a role for collapsin response mediator protein (Crmp-2), a neuronal protein implicated in axonal outgrowth and a component of the semaphorin 3A pathway, in switching GTPase signaling when expressed in combination with either dominant active Rac or Rho. In neuroblastoma N1E-115 cells, co-expression of Crmp-2 with dominant active RhoA V14 induced Rac morphology, cell spreading and ruffling (and the formation of neurites).
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