Open AccessMAPK pathway activation in the embryonic pituitary results in stem cell compartment expansion, differentiation defects and provides insights into the pathogenesis of papillary craniopharyngioma
Author(s) -
Scott Haston,
Sara Pozzi,
Gabriela Carreno,
Saba Manshaei,
Leonidas Panousopoulos,
José Mario González-Meljem,
John Apps,
Alex Virasami,
Selvam Thavaraj,
Alice Gutteridge,
Tim Forshew,
Richard Marais,
Sebastian Brandner,
Thomas S. Jacques,
Cynthia L. Andoniadou
Publication year - 2017
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.150490
Subject(s) - biology , sox2 , pituitary gland , cellular differentiation , stem cell , cancer research , mapk/erk pathway , corticotropic cell , microbiology and biotechnology , embryonic stem cell , endocrinology , medicine , signal transduction , genetics , hormone , gene
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.