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 Schwann cell generation is regulated by the balance of two opposing signals, β neuregulins and endothelins. The β neuregulins promote the development of precursors to Schwann cells whereas endothelins retard it through an action on endothelin-B receptors. The present work has shown additional controls of this transition, and implicates AP-2 transcription factors, in particular AP-2α, as negative regulators of Schwann cell generation. We found that both AP-2α and AP-2γ are present in early embryonic nerves, whereas AP-2β was not. Isoform-specific analysis of AP-2α showed that isoform 3 was most abundant with isoforms 1 and 2 present in lesser amounts; isoform 4 was absent. Maximal AP-2α and AP-2γ mRNA expression 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 the nerve. In both rats and in mice, in vivo and in vitro, downregulation of AP-2α mRNA and protein coincided with one of the main steps in Schwann cell development, the precursor-Schwann cell transition. Moreover, Schwann cell generation was delayed if this downregulation was prevented by enforced expression of AP-2α in precursors. These studies suggest that AP-2 is involved in the control of the timing of Schwann cell development.