Figure 1.

A two-stage model for the context-dependent effects of hedgehog signaling in the mammary regenerative hierarchy. We propose a model in which hedgehog signaling on mammary stem cells is sufficient to overcome mammary stem cell quiescence. This effect may be mediated by subverting mechanisms governing entry into or maintenance of quiescence. In this case, hedgehog activation is not directly mitogenic but would potentiate a proliferative response to mitogenic signals within the surrounding milieu. Alternatively hedgehog activation may be directly mitogenic in mammary stem cells. Following the elaboration of mammary progenitors hedgehog activation may mediate cell fate specification, cellular differentiation and growth arrest. This model may account for the observation that hedgehog activation stimulates mammosphere formation in vitro and disrupts long term BrdU retention in vivo in enriched fractions of mammary stem cells (Lin⁻/CD24⁺/CD29^high). This model may also account for the observation that hedgehog activation in mammary progenitors ablates mammosphere formation and the separate observation of decreased engraftment efficiency by MECs from the MMTV-SmoM2 model. This model also raised specific questions regarding the factors within mammary stem cells and mammary progenitors that mediate this differential two stage response.