Inhibition by Wnt-1 or Wnt-3a of nerve growth factor-induced differentiation of PC12 cells is reversed by bisindolylmaleimide-I but not by several other PKC inhibitors.

Wnt-1 and Wnt-3a exhibit redundancy in neural crest development. We have found that they do not produce the same effects on PC12 cells, which were obtained from the adrenal medulla, a neural crest derivative. However, both Wnt-1 or Wnt-3a inhibit nerve growth factor (NGF)-induced neurite outgrowth. The inhibition is reversed by the protein kinase C (PKC) inhibitor, bisindolylmaleimide-I, but it did not reverse Wnt-1-induced activation of the canonical Wnt pathway. The Wnt-1 inhibitory effect was not reversed by several other PKC inhibitors, by phorbol ester-induced down-regulation of PKC, or by pertussis toxin, which is known to inhibit another Wnt signaling pathway, the Wnt/Ca(2+) pathway. We suggest that bisindolylmaleimide-I acts by affecting either a pathway downstream from Lef-1/Tcf in the canonical pathway or a Wnt signaling pathway other than the canonical pathway. In either case, the bisindolylmaleimide-I sensitivity of this pathway should aid in its identification.