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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.
Haston, S Pozzi, S Carreno, G Manshaei, S Panousopoulos, L Gonzalez-Meljem, J Apps, J R Virasami, A Thavaraj, S Gutteridge, A
Haston, S
Pozzi, S
Carreno, G
Manshaei, S
Panousopoulos, L
Gonzalez-Meljem, J
Apps, J R
Virasami, A
Thavaraj, S
Gutteridge, A
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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.
Authors
Haston, S
Pozzi, S
Carreno, G
Manshaei, S
Panousopoulos, L
Gonzalez-Meljem, J
Apps, J R
Virasami, A
Thavaraj, S
Gutteridge, A
Forshew, T
Marais, Richard
Brandner, S
Jacques, T
Andoniadou, C
Martinez-Barbera, J
Pozzi, S
Carreno, G
Manshaei, S
Panousopoulos, L
Gonzalez-Meljem, J
Apps, J R
Virasami, A
Thavaraj, S
Gutteridge, A
Forshew, T
Marais, Richard
Brandner, S
Jacques, T
Andoniadou, C
Martinez-Barbera, J
Affiliation
Developmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK
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Date
2017-05-15
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Article
Citation
MAPK pathway activation in the embryonic pituitary results in stem cell compartment expansion, differentiation defects and provides insights into the pathogenesis of papillary craniopharyngioma. 2017 Development