ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2010) 24 OC1.7

Enhancement of the canonical Wnt pathway in Rathke's pouch results in pituitary tumours reminiscent of human adamantinomatous craniopharyngioma

Carles Gaston-Massuet1,2,3, Cynthia Andoniadou1,2,3, Massimo Signore1,2,3, Sujatha Jayakody1,2,3, Nocoletta Charolidi1,2,3, Paul Le Tissier1,2,3, Mehul Dattani1,2,3 & Juan Pedro Martinez-Barbera1,2,3

1Neural Development Unit, Institute of Child Health, London, UK; 2National Institute for Medical Research, Division of Molecular Neuroendocrinology, London, UK; 3Clinical Molecular Genetics Unit, Institute of Child Health, London, UK.

Wnt/beta-catenin signalling pathway is required during embryonic development for normal cell proliferation, differentiation and for organ homeostasis in adulthood. Over-activation of this pathway has been implicated in human cancers such as colon or skin cancers. Here, we demonstrate that enhancement of the Wnt pathway in the embryonic Rathke’s pouch causes over-proliferation of progenitor cells and severe differentiation defects in the Pit1-lineage, which results in extreme growth retardation and hypopituitarism. Mutant mice mostly die perinatally but those that survive weaning develop lethal pituitary tumors. Histopathological analysis revealed that these murine tumors most closely resemble human adamantinomatous craniopharyngioma rather than any other pituitary tumor, including pituitary adenomas, Rathke’s cleft cysts, xanthogranulomas, posterior pituitary tumors (e.g. pituitocytomas) or even the adult (papillary) form of craniopharyngioma. This tumorogenic effect only occurs when Wnt pathway over-activation occurs in the early Rathke’s pouch progenitors, but not when committed or differentiated cells are targeted. Together, our findings provide new insights into the roles of the Wnt pathway in the control of pituitary cell proliferation and demonstrate, for the first time, a causative role the Wnt pathway in an undifferentiated multipotent pituitary progenitor in the genesis of murine pituitary tumors that are reminiscent of human craniopharyngioma