Developmental regulation and overexpression of the transcription factor AP-2, a potential regulator of the timing of Schwann cell generation

There is now evidence from in vivo and in vitro studies that the rate of Sc hwann cell generation is regulated by the balance of two opposing signals, beta neuregulins and endothelins. The beta neuregulins promote the developm ent of precursors to Schwann cells whereas endothelins retard it through an action on endothelin-B receptors. The present work has shown additional co ntrols of this transition, and implicates AP-2 transcription factors, in pa rticular AP-2 alpha, as negative regulators of Schwann cell generation. We found that both AP-2 alpha and AP-2 gamma are present in early embryonic ne rves, whereas AP-2 beta was not. Isoform-specific analysis of AP-2 alpha sh owed that isoform 3 was most abundant with isoforms 1 and 2 present in less er amounts; isoform 4 was absent. Maximal AP-2 alpha and AP-2 gamma mRNA ex pression occurred at embryonic day (E) 12/13 in the mouse and at E14/15 in the rat, which correlates with the presence of Schwann cell precursors in t he nerve. In both rats and in mice, in vivo and in vitro, downregulation of AP-2 alpha mRNA and protein coincided with one of the main steps in Schwan n cell development, the precursor-Schwann cell transition. Moreover, Schwan n cell generation was delayed if this downregulation was prevented by enfor ced expression of AP-2 alpha in precursors. These studies suggest that AP-2 is involved in the control of the timing of Schwann cell development.