REGULATION OF SENSORY NEURON PRECURSOR PROLIFERATION BY CYCLIC GMP-DEPENDENT PROTEIN-KINASE

Cyclic GMP (cGMP) is a molecular messenger involved in diverse cellula r processes. Recently, cGMP-dependent protein kinase (cGK) type II was determined to be a regulator of endochondral ossification and bone gr owth, identifying a role for cGMP in the regulation of cellular prolif eration. Here, we demonstrate the presence of cGK type I (cGKI) in cel ls of the developing trigeminal ganglia. cGKI occurs in some prolifera ting precursors as evidenced by double labeling with an antibody to cG KI and 5-bromo-2'-deoxyuridine(BrdU) incorporation. Inhibition of cGKI with KT5823 or Rp-8-(4-chlorophenylthio)guanosine-3',5' p-cyclic mono phosphorothioate (Rp-8-pCPT-cGMPS) in chick embryos results in a 30-40 % decrease in trigeminal ganglia cell number, and this effect is indep endent of nitric oxide synthase (NOS). In addition, inhibition of cGKI with Rp-8-pCPT-cGMPS results in a 60% decrease in BrdU incorporation in the trigeminal ganglia of embryonic day 5 chicks. We find that PC12 cells expressing cGKI proliferate more rapidly and incorporate more B rdU than do control cells. The cGKI inhibitor Rp-8-pCPT-cGMPS decrease s proliferation and BrdU incorporation in transfected PC12 cells but h as no effect on control cells. The PC12 cells do not express NOS, indi cating that this effect is also independent of NOS. Thus, cGKI regulat es the proliferation of sensory neurons as a result of activation of a NOS-independent pathway, representing a novel pathway by which the nu mber of sensory neurons is regulated.