Show simple item record

dc.contributor.authorHaston, S
dc.contributor.authorPozzi, S
dc.contributor.authorCarreno, G
dc.contributor.authorManshaei, S
dc.contributor.authorPanousopoulos, L
dc.contributor.authorGonzalez-Meljem, J
dc.contributor.authorApps, J R
dc.contributor.authorVirasami, A
dc.contributor.authorThavaraj, S
dc.contributor.authorGutteridge, A
dc.contributor.authorForshew, T
dc.contributor.authorMarais, Richard
dc.contributor.authorBrandner, S
dc.contributor.authorJacques, T
dc.contributor.authorAndoniadou, C
dc.contributor.authorMartinez-Barbera, J
dc.date.accessioned2017-06-29T10:43:02Z
dc.date.available2017-06-29T10:43:02Z
dc.date.issued2017-05-15
dc.identifier.citationMAPK pathway activation in the embryonic pituitary results in stem cell compartment expansion, differentiation defects and provides insights into the pathogenesis of papillary craniopharyngioma. 2017 Developmenten
dc.identifier.issn1477-9129
dc.identifier.pmid28506993
dc.identifier.doi10.1242/dev.150490
dc.identifier.urihttp://hdl.handle.net/10541/620428
dc.description.abstractDespite 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.isoenen
dc.rightsArchived with thanks to Development (Cambridge, England)en
dc.titleMAPK 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.typeArticleen
dc.contributor.departmentDevelopmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UKen
dc.identifier.journalDevelopmenten
refterms.dateFOA2020-04-27T13:09:15Z
html.description.abstractDespite 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.


Files in this item

Thumbnail
Name:
559543.pdf
Size:
23.64Mb
Format:
PDF
Description:
CORE by link

This item appears in the following Collection(s)

Show simple item record