Journal
DEVELOPMENT
Volume 144, Issue 12, Pages 2141-2152Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.150490
Keywords
Pituitary development; Mouse; Papillary craniopharyngioma; Sox2; Tumour
Categories
Funding
- Medical Research Council (MRC) [MR/M000125/1, MR/L016729/1]
- National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children National Health Service Foundation Trust
- University College London
- Wellcome Trust
- Cancer Research UK [23615, 22902, S_1731] Funding Source: researchfish
- Children with Cancer UK [15-190] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [W1055] Funding Source: researchfish
- Medical Research Council [MC_PC_15004, G0700089, MR/M000125/1, MR/L016729/1] Funding Source: researchfish
- The Brain Tumour Charity [GN-000382] Funding Source: researchfish
- MRC [G1100578, MC_PC_15004, G0701018, MR/N004272/1, G0700089] Funding Source: UKRI
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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.
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