B-Raf Is Required for Hypothalamic-Pituitary Axis Development and Activation Leads to Hypopituitarism in Mice
Presentation Number: SAT 439
Date of Presentation: April 1st, 2017
Nikolina Kyprianou*1, Eugenia Marinelli2, Angelica Gualtieri3, Valeria Scagliotti4, Lilliana Vignola2, Louise Cheryl Gregory5, Shannon William Davis6, Mehul Tulsidas Dattani7, Evelien F Gevers8 and Carles Gaston-Massuet9
1William Harvey Research Institute, Queen Mary University of London, LONDON, United Kingdom, 2William Harvey Research Institute, Queen Mary University of London, London, United Kingdom, 3William Harvey Research Insitute, Barts & the London, London, United Kingdom, 4William Harvey Research Institue, Barts & The London, London, United Kingdom, 5UCL Institute of Child Health, London, United Kingdom, 6University of South Carolina, Columbia, SC, 7UCL GOS Institute of Child Health, London, United Kingdom, 8William Harvey Research Institute / Barts Health NHS Trust, London, United Kingdom, 9William Harvey Research Institute, London, United Kingdom
B-Raf is a protein kinase component of the RAS/MAPK signaling pathway, which is involved in cell division, proliferation and survival. Somatic mutations in BRAF, encoding for B-Raf, have been described in multiple tumors and recently papillary craniopharyngiomas. Germline mutations in components of this pathway are found in RASopathies, which are a group of congenital conditions including Noonan, Costello and Cardiofaciocutaneous syndrome characterized by CNS, cardiac and facial abnormalities. Interestingly, endocrinopathies have been linked to RASopathies including short stature due to GH deficiency and delayed puberty, suggesting a role for B-Raf in Hypothalamic Pituitary Axis (HP-axis) development. We hypothesized that BRAF is essential for normal development of the HP-axis in murine models. We have taken a murine transgenic approach to express oncogenic BrafV600E in a pituitary specific fashion by using a pituitary Cre reporter line, Prop1:Cre. Both embryos and pups were studied in order to assess the phenotype of the Prop1:Cre;BrafV600E/+ mouse. The growth of mutant pups was assessed by taking daily weight readings (n=10). Their pituitaries were extracted following culling and compared to their wild type same-sex littermates (n=8). Embryos were collected at different gestational ages to assess the role of oncogenic Braf in cell lineage determination and terminal differentiation of hormone producing cells. Prop1:Cre;BrafV600E/+ mutant pups exhibited dwarfism with reduced size and weight compared with control littermates suggesting a functional compromise of the HP-axis. We found that the integrity of the HP-axis is severely affected from early stages of development, with hyperplasia of pituitary progenitors leading to multiple clefts and increased mitotic index. Cell lineage differentiation markers showed severe delay and terminal differentiation of hormone producing cells was severely compromised leading to dwarfism in the Prop1:Cre;BrafV600E/+ mutants. Our data uncover a previously unreported role for B-Raf in pituitary development and show that the activating BrafV600E mutation in the undifferentiated pituitary progenitor cells leads to hypopituitarism. Our findings incorporate the RAS/MAPK pathway in HP-axis development and show a direct and vital role for B-Raf in HP-axis development.
Nothing to Disclose: NK, EM, AG, VS, LV, LCG, SWD, MTD, EFG, CG