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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, JM; Apps, JR; ... Martinez-Barbera, JP; + view all (2017) MAPK pathway activation in the embryonic pituitary results in stem cell compartment expansion, differentiation defects and provides insights into the pathogenesis of papillary craniopharyngioma. Development , 144 pp. 2141-2152. 10.1242/dev.150490.

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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.

Type: Article
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.
Location: England
DOI: 10.1242/dev.150490
Publisher version: http://doi.org/10.1242/dev.150490
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Pituitary, Sox2, development, mouse, papillary craniopharyngioma, tumour.
UCL classification: UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Neurodegenerative Diseases
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Wolfson Institute and Cancer Institute Administration > Cancer Institute
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health
URI: http://discovery.ucl.ac.uk/id/eprint/1556389
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