title: SOX2 is sequentially required for progenitor proliferation and lineage specification in the developing pituitary.
abstract: Sox2 mutations are associated with pituitary hormone deficiencies and the protein is required for pituitary progenitor proliferation, but its function has not been well characterized in this context. SOX2 is known to activate expression of Six6, encoding a homeodomain transcription factor, in the ventral diencephalon. Here, we find that the same relationship likely exists in the pituitary. Moreover, because Six6 deletion is associated with a similar phenotype as described here for loss of Sox2, Six6 appears to be an essential downstream target of SOX2 in the gland. We also uncover a second role for SOX2. Whereas cell differentiation is reduced in Sox2 mutants, some endocrine cells are generated, such as POMC-positive cells in the intermediate lobe. However, loss of SOX2 here results in complete downregulation of the melanotroph pioneer factor PAX7, and subsequently a switch of identity from melanotrophs to ectopic corticotrophs. Rescuing proliferation by ablating the cell cycle negative regulator p27 (also known as Cdkn1b) in Sox2 mutants does not restore melanotroph emergence. Therefore, SOX2 has two independent roles during pituitary morphogenesis; firstly, promotion of progenitor proliferation, and subsequently, acquisition of melanotroph identity.
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Sam
authors.initials: S
authors.lastname: Goldsmith
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA, UK robin.lovell-badge@crick.ac.uk karine.rizzoti@crick.ac.uk.
authors.forename: Robin
authors.identifier: 0000-0001-9364-4179
authors.initials: R
authors.lastname: Lovell-Badge
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA, UK robin.lovell-badge@crick.ac.uk karine.rizzoti@crick.ac.uk.
authors.forename: Karine
authors.identifier: 0000-0003-0711-5452
authors.initials: K
authors.lastname: Rizzoti
mesh_terms: D000818:Animals; D002452:Cell Count; D019070:Cell Lineage; D049109:Cell Proliferation; D052680:Corticotrophs / Q000166:cytology / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D052717:Melanotrophs / Q000166:cytology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009024:Morphogenesis / Q000235:genetics; D051763:PAX7 Transcription Factor / Q000378:metabolism; D010902:Pituitary Gland / Q000166:cytology* / Q000196:embryology*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: C489733:Hesx1 protein, mouse; D018398:Homeodomain Proteins; D051763:PAX7 Transcription Factor; D012333:RNA, Messenger; D012097:Repressor Proteins; D055748:SOXB1 Transcription Factors; C114419:Six6 protein, mouse; D015534:Trans-Activators; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011333:Pro-Opiomelanocortin
keywords: Cell fate; Morphogenesis; Pituitary; Progenitor; SOX