Divergent regulation of GAP-43 expression and CNS neurite outgrowth by cyclic AMP

Robust process outgrowth and high expression of the growth-associated prote in GAP-43 seem to be intrinsic features of neurons, but both ave down-regul ated after axonal contact of target cells. We report that chronic exposure of the serotonergic CNS cell line RN46A to cyclic AMP analogs, forskolin, o r cholera toxin represses GAP-43 expression in a dose dependent manner. Thu s, cAMP could mediate a GAP-43 repressive signal that is initiated extracel lularly. Activation of the cyclic AMP pathway by these same reagents, howev er, enhances the rate that RN46A cells extend neurites, This stimulation of neurite growth can occur during inhibition of new transcription, and in th e absence of high levels of GAP-43. These findings demonstrate that a GAP-4 3-repressing intracellular signaling pathway exists, that repression of GAP -43 expression by cAMP is not directly coupled to inhibition of neurite gro wth, and that acceleration of growth cone advancement by cAMP is not depend ent on the presence of GAP-43. (C) 2000 Wiley-Liss, Inc.