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MAPK pathway activation in the embryonic pituitary results in stem cell compartment expansion, differentiation defects and provides insights into the pathogenesis of papillary craniopharyngioma

Development2017Vol. 144(12), pp. 2141–2152

Citations Over TimeTop 10% of 2017 papers

Scott Haston, Sara Pozzi, Gabriela Carreno, Saba Manshaei, Leonidas Panousopoulos, José Mario González-Meljem, J. R. Apps, Alex Virasami, Selvam Thavaraj, Alice Gutteridge, Tim Forshew, Richard Marais, Sebastian Brandner, Thomas S. Jacques, Cynthia L. Andoniadou, Juan Pedro Martı́nez-Barberá

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+ 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+ cells with sustained proliferative capacity and disrupted pituitary differentiation. Together, our data demonstrate a crucial function of the MAPK pathway in controlling the balance between proliferation and differentiation of Sox2+ cells and suggest that persistent proliferative capacity of Sox2+ cells may underlie the pathogenesis of PCP.

Citations Over TimeTop 10% of 2017 papers

Abstract

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