MAPK pathway control of stem cell proliferation and differentiation in the embryonic pituitary provides insights into the pathogenesis of papillary craniopharyngioma

Scott Haston, Sara Pozzi, Gabriela Carreno, Saba Manshaei, Leonidas Panousopoulos, Jose Mario Gonzalez-Meljem, John R Apps, Alex Virasami, Selvam Thavaraj, Alice Gutteridge, Tim Forshew, Richard Marais, Sebastian Brandner, Thomas S Jacques, Cynthia L Andoniadou, Juan Pedro Martinez-Barbera

Research output: Contribution to journalArticlepeer-review

71 Citations (Scopus)
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Abstract

Despite the importance of the RAS-RAF-MAPK pathway in normal physiology and disease of numerous organs, its role during pituitary development and tumourigenesis remains largely unknown. Here we show that the over-activation of the MAPK pathway, through conditional expression of the gain-of-function alleles BrafV600E and KrasG12D in the developing mouse pituitary, results in severe hyperplasia and abnormal morphogenesis of the gland by the end of gestation. Cell-lineage commitment and terminal differentiation are disrupted, leading to a significant reduction in numbers of most of the hormone-producing cells before birth, with the exception of corticotrophs. Of note, Sox2+ve stem cells and clonogenic potential are drastically increased in the mutant pituitaries. Finally, we reveal that papillary craniopharyngioma (PCP), a benign human pituitary tumour harbouring BRAF p.V600E also contains Sox2+ve cells with sustained proliferative capacity and disrupted pituitary differentiation. Together, our data demonstrate a critical function of the MAPK pathway in controlling the balance between proliferation and differentiation of Sox2+ve cells and suggest that persistent proliferative capacity of Sox2+ve cells may underlie the pathogenesis of PCP.

Original languageEnglish
Pages (from-to)2141-2152
JournalDevelopment
Volume144
Issue number12
Early online date15 May 2017
DOIs
Publication statusPublished - 15 Jun 2017

Keywords

  • Journal Article

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