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

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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 + 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.

          Abstract

          [Related article:] Highlighted Article: Constitutive activation of the MAPK/ERK pathway causes pituitary hyperplasia, abnormal morphogenesis, and abnormal endocrine cell specification due to the sustained proliferation of the Sox2 + stem cell compartment.

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          Most cited references32

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          Mutations in the deubiquitinase gene USP8 cause Cushing's disease.

          Cushing's disease is caused by corticotroph adenomas of the pituitary. To explore the molecular mechanisms of endocrine autonomy in these tumors, we performed exome sequencing of 10 corticotroph adenomas. We found somatic mutations in the USP8 deubiquitinase gene in 4 of 10 adenomas. The mutations clustered in the 14-3-3 protein binding motif and enhanced the proteolytic cleavage and catalytic activity of USP8. Cleavage of USP8 led to increased deubiqutination of the EGF receptor, impairing its downregulation and sustaining EGF signaling. USP8 mutants enhanced promoter activity of the gene encoding proopiomelanocortin. In summary, our data show that dominant mutations in USP8 cause Cushing's disease via activation of EGF receptor signaling.
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            Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects.

            Activating mutations in the ras oncogene are not considered sufficient to induce abnormal cellular proliferation in the absence of cooperating oncogenes. We demonstrate that the conditional expression of an endogenous K-ras(G12D) allele in murine embryonic fibroblasts causes enhanced proliferation and partial transformation in the absence of further genetic abnormalities. Interestingly, K-ras(G12D)-expressing fibroblasts demonstrate attenuation and altered regulation of canonical Ras effector signaling pathways. Widespread expression of endogenous K-ras(G12D) is not tolerated during embryonic development, and directed expression in the lung and GI tract induces preneoplastic epithelial hyperplasias. Our results suggest that endogenous oncogenic ras is sufficient to initiate transformation by stimulating proliferation, while further genetic lesions may be necessary for progression to frank malignancy.
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              Increased Wingless ( Wnt ) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans

              Wingless (Wnt)/β-catenin signaling plays an essential role during normal development, is a critical regulator of stem cells, and has been associated with cancer in many tissues. Here we demonstrate that genetic expression of a degradation-resistant mutant form of β-catenin in early Rathke's pouch (RP) progenitors leads to pituitary hyperplasia and severe disruption of the pituitary-specific transcription factor 1-lineage differentiation resulting in extreme growth retardation and hypopituitarism. Mutant mice mostly die perinatally, but those that survive weaning develop lethal pituitary tumors, which closely resemble human adamantinomatous craniopharyngioma, an epithelial tumor associated with mutations in the human β-catenin gene. The tumorigenic effect of mutant β-catenin is observed only when expressed in undifferentiated RP progenitors, but tumors do not form when committed or differentiated cells are targeted to express this protein. Analysis of affected pituitaries indicates that expression of mutant β-catenin leads to a significant increase in the total numbers of pituitary progenitor/stem cells as well as in their proliferation potential. Our findings provide insights into the role of the Wnt pathway in normal pituitary development and demonstrate a causative role for mutated β-catenin in an undifferentiated RP progenitor in the genesis of murine and human craniopharyngioma.
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                Author and article information

                Journal
                Development
                Development
                DEV
                develop
                Development (Cambridge, England)
                The Company of Biologists Ltd
                0950-1991
                1477-9129
                15 June 2017
                15 December 2017
                : 144
                : 12
                : 2141-2152
                Affiliations
                [1 ] Developmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London , London WC1N 1EH, UK
                [2 ] Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust , London WC1N 3NN, UK
                [3 ] Head and Neck Pathology, Dental Institute, King's College London , London SE1 9RT, UK
                [4 ] Department of Pathology, UCL Cancer Institute , London WC1E 6DD, UK
                [5 ] Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester , Manchester M20 4BX, UK
                [6 ] Department of Neurodegenerative Disease, UCL Institute of Neurology , Queen Square, London WC1N 3BG, UK
                [7 ] Division of Neuropathology, The National Hospital for Neurology and Neurosurgery , Queen Square, London WC1N 3BG, UK
                [8 ] Centre for Craniofacial and Regenerative Biology, King's College London , London SE1 9RT, UK
                [9 ] Department of Internal Medicine III, Technische Universität Dresden , Dresden 01307, Germany
                Author notes
                Author information
                http://orcid.org/0000-0003-3928-4808
                http://orcid.org/0000-0002-5292-7276
                Article
                PMC5482995 PMC5482995 5482995 DEV150490
                10.1242/dev.150490
                5482995
                28506993
                6266c6c5-8908-429c-b153-9a1467efc6e7
                © 2017. Published by The Company of Biologists Ltd
                History
                : 13 February 2017
                : 3 May 2017
                Funding
                Funded by: Medical Research Council;
                Funded by: National Institute for Health Research Biomedical Research Centre;
                Funded by: Great Ormond Street Hospital for Children, http://dx.doi.org/10.13039/501100003784;
                Funded by: University College London, http://dx.doi.org/10.13039/501100000765;
                Funded by: Cancer Research UK, http://dx.doi.org/10.13039/501100000289;
                Funded by: Wellcome Trust, http://dx.doi.org/10.13039/100004440;
                Categories
                203
                Stem Cells and Regeneration

                Mouse,Papillary craniopharyngioma,Sox2,Tumour,Pituitary development

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