Room 133 (Moscone Center)
Methods: We have generated a tamoxifen-inducible Cre strain under the control of Sox2 regulatory elements (Sox2-CreERT2) and used this in combination with the R26-YFP reporter to follow the fates of descendants of SOX2+ cells after tamoxifen induction at embryonic and adult stages. In addition, we induced targeted expression of constitutive active β-catenin specifically in SOX2+ stem cells in Sox2CreERT2/+;Ctnnb1lox(ex3)/+;R26YFP/+ mice to determine if activation of the canonical WNT pathway in the SOX2+population leads to tumors.
Results: Using genetic lineage tracing, we show for the first time in vivo, that the SOX2+ cell compartment in both the embryonic and adult pituitary contains long-lived multipotent stem cells able to differentiate into all hormone-producing lineages and contribute to organ homeostasis during postnatal life. In addition, we demonstrate that the targeted expression of constitutive active β-catenin specifically in SOX2+stem cells gives rise to non-functioning pituitary tumors. Unexpectedly, the tumor mass is not derived from the mutation-sustaining cells, as revealed by lineage tracing. Instead, mutation-sustaining cells express secreted factors such as BMPs, FGFs and SHH, which can stimulate proliferation.
Conclusions: We uncover a novel mechanism by which SOX2+ stem cells initiate pituitary oncogenesis in a paracrine manner as well as provide in vivo evidence for the contribution of SOX2+ cells in the long-term physiological cell turnover of the adult pituitary.
Nothing to Disclose: CLA, PRL, LHP, MTD, JPM
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