Wnt-1 inhibits nerve growth factor-induced differentiation of PC12 cells by preventing the induction of some but not all late-response genes

The vertebrate Wnt-1 proto-oncogene is expressed transiently in embryonic b rain and functions in the development of the central nervous system and neu ral crest. The role of Wnt-1 in neural crest development appears to be to i ncrease the number of certain progenitor cells by preventing their prematur e differentiation. To study the mechanism by which this transient Wnt-1 exp ression inhibits differentiation we have constructed PC12 pheochromocytoma cells in which Wnt-1 expression levels were controlled by use of a tetracyc line-responsive transactivator. Induction of Wnt-1 expression by tetracycli ne withdrawal was followed by activation of the Wnt-1 signalling pathway as shown by activation of the Lef-1/Tcf transcription factor. Wnt-1 expressio n by these cells resulted in reversible inhibition of NGF-induced neurite o utgrowth, but it did not adversely affect the maintenance of previously for med NGF-induced neurites. Wnt-1 expression also partially blocked the abili ty of NGF to decrease the rate of cell multiplication. Wnt-1 decreased the NGF-induced expression of the late-response gene SCG10 but not of the immed iate early genes, fos, Nur77 and UPAR (urokinase-type plasminogen activator receptor) nor of the late-response genes GAP-43 and collagenase. The Wnt-1 expressing PC12 cells multiplied at a greater rate when they expressed Wnt -1 than they did in the absence of Wnt-1 expression, a result that is consi stent with the proposal that Wnt-1 may also act as a mitogen. (C) 2000 Else vier Science B.V. All rights reserved.