Identification of an unexpected link between the Shh pathway and a G2/M regulator, the phosphatase CDC25B

Abstract

Sonic hedgehog (Shh) signaling controls numerous aspects of vertebrate development, including proliferation of precursors in different organs. Identification of molecules that link the Shh pathway to cell cycle machinery is therefore of major importance for an understanding of the mechanisms underlying Shh-dependent proliferation. Here, we show that an actor in the control of entry into mitosis, the phosphatase CDC25B, is transcriptionally upregulated by the Shh/Gli pathway. Unlike other G2/M regulators, CDC25B is highly expressed in domains of Shh activity, including the ventral neural tube and the posterior limb bud. Loss- and gain-of-function experiments reveal that Shh contributes to CDC25B transcriptional activation in the neural tube both of chick and mouse embryos. Moreover, CDC25B transcripts are absent from the posterior limb bud of Shh-/- mice, while anterior grafts of Shh-expressing cells in the chicken limb bud induce ectopic CDC25B expression. Arresting the cell cycle does not reduce the level of CDC25B expression in the neural tube strongly suggesting that the upregulation of CDC25B is not an indirect consequence of the Shh-dependent proliferation. These data reveal an unexpected developmental link between the Shh pathway and a participant in G2/M control.