MAPK pathway activation in the embryonic pituitary results in stem cell compartment expansion, differentiation defects and provides insights into the pathogenesis of papillary craniopharyngioma.
dc.contributor.author | Haston, S | |
dc.contributor.author | Pozzi, S | |
dc.contributor.author | Carreno, G | |
dc.contributor.author | Manshaei, S | |
dc.contributor.author | Panousopoulos, L | |
dc.contributor.author | Gonzalez-Meljem, J | |
dc.contributor.author | Apps, J R | |
dc.contributor.author | Virasami, A | |
dc.contributor.author | Thavaraj, S | |
dc.contributor.author | Gutteridge, A | |
dc.contributor.author | Forshew, T | |
dc.contributor.author | Marais, Richard | |
dc.contributor.author | Brandner, S | |
dc.contributor.author | Jacques, T | |
dc.contributor.author | Andoniadou, C | |
dc.contributor.author | Martinez-Barbera, J | |
dc.date.accessioned | 2017-06-29T10:43:02Z | |
dc.date.available | 2017-06-29T10:43:02Z | |
dc.date.issued | 2017-05-15 | |
dc.identifier.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 | en |
dc.identifier.issn | 1477-9129 | |
dc.identifier.pmid | 28506993 | |
dc.identifier.doi | 10.1242/dev.150490 | |
dc.identifier.uri | http://hdl.handle.net/10541/620428 | |
dc.description.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. | |
dc.language.iso | en | en |
dc.rights | Archived with thanks to Development (Cambridge, England) | en |
dc.title | MAPK pathway activation in the embryonic pituitary results in stem cell compartment expansion, differentiation defects and provides insights into the pathogenesis of papillary craniopharyngioma. | en |
dc.type | Article | en |
dc.contributor.department | Developmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK | en |
dc.identifier.journal | Development | en |
refterms.dateFOA | 2020-04-27T13:09:15Z | |
html.description.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. |