Neural Development Unit, University College London Institute of Child Health, London WC1N 1EH, United Kingdom.
Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11482-7. doi: 10.1073/pnas.1101553108. Epub 2011 Jun 2.
Wingless (Wnt)/β-catenin signaling plays an essential role during normal development, is a critical regulator of stem cells, and has been associated with cancer in many tissues. Here we demonstrate that genetic expression of a degradation-resistant mutant form of β-catenin in early Rathke's pouch (RP) progenitors leads to pituitary hyperplasia and severe disruption of the pituitary-specific transcription factor 1-lineage differentiation resulting in extreme growth retardation and hypopituitarism. Mutant mice mostly die perinatally, but those that survive weaning develop lethal pituitary tumors, which closely resemble human adamantinomatous craniopharyngioma, an epithelial tumor associated with mutations in the human β-catenin gene. The tumorigenic effect of mutant β-catenin is observed only when expressed in undifferentiated RP progenitors, but tumors do not form when committed or differentiated cells are targeted to express this protein. Analysis of affected pituitaries indicates that expression of mutant β-catenin leads to a significant increase in the total numbers of pituitary progenitor/stem cells as well as in their proliferation potential. Our findings provide insights into the role of the Wnt pathway in normal pituitary development and demonstrate a causative role for mutated β-catenin in an undifferentiated RP progenitor in the genesis of murine and human craniopharyngioma.
Wingless (Wnt)/β-catenin 信号通路在正常发育过程中起着至关重要的作用，是干细胞的关键调节因子，并且与许多组织中的癌症有关。在这里，我们证明在早期 Rathke 囊（RP）祖细胞中遗传表达一种降解抗性突变形式的 β-catenin 会导致垂体增生，并严重破坏垂体特异性转录因子 1 谱系分化，导致生长迟缓和垂体功能减退。突变小鼠大多在围产期死亡，但那些存活到断奶的小鼠会发展出致命的垂体肿瘤，这些肿瘤与人类β-catenin 基因突变密切相关，是一种与人类β-catenin 基因突变相关的上皮肿瘤。只有在未分化的 RP 祖细胞中表达突变的β-catenin 时，才会观察到其致瘤作用，但当靶向表达该蛋白的定向或分化细胞时，肿瘤不会形成。对受影响的垂体的分析表明，突变β-catenin 的表达导致垂体祖细胞/干细胞的总数以及其增殖潜力显著增加。我们的研究结果提供了对 Wnt 途径在正常垂体发育中的作用的深入了解，并证明了突变的β-catenin 在未分化的 RP 祖细胞中在发生鼠和人类颅咽管瘤中的因果作用。
