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.
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