MAPK pathway control of stem cell proliferation and differentiation in the embryonic pituitary provides insights into the pathogenesis of papillary craniopharyngioma

Development. 2017 Jun 15;144(12):2141-2152. doi: 10.1242/dev.150490. Epub 2017 May 15.


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.

Keywords: Mouse; Papillary craniopharyngioma; Pituitary development; Sox2; Tumour.

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Craniopharyngioma / genetics
  • Craniopharyngioma / pathology
  • Craniopharyngioma / physiopathology*
  • Embryonic Stem Cells / pathology
  • Embryonic Stem Cells / physiology
  • Female
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Pituitary Gland / cytology
  • Pituitary Gland / embryology
  • Pituitary Gland / enzymology
  • Pituitary Neoplasms / genetics
  • Pituitary Neoplasms / pathology
  • Pituitary Neoplasms / physiopathology*
  • Pregnancy
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • SOXB1 Transcription Factors / metabolism


  • Hesx1 protein, mouse
  • Homeodomain Proteins
  • Mutant Proteins
  • Repressor Proteins
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • Braf protein, mouse
  • Proto-Oncogene Proteins B-raf
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)