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Title: The role of SOX2 in pituitary development
Author: Goldsmith, S.
ISNI:       0000 0004 5359 0753
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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SOX2 is expressed in the pituitary anlagen, Rathke’s Pouch (RP), from its induction at 9.0dpc. RP progenitors initially expand, later giving rise to all pituitary cell types. As cells differentiate, SOX2 expression is down-regulated, but a population of SOX2+ve cells persists until adulthood. These represent adult stem cells, displaying regenerative potential upon physiological demand. In humans and mice, heterozygous loss-of-function mutations in SOX2/Sox2 are associated with hypopituitarism. It was therefore decided to investigate the role of SOX2 during murine pituitary development. Homozygous null mutations of Sox2 lead to embryo lethality following implantation; consequently conditional strategies were used to delete the gene specifically in RP. Nkx3.1Cre and FoxG1Cre, display different spatio-temporal patterns of activity in RP. The severity in hypoplasia and reduced progenitor cell proliferation correlated with the efficiency and timing of Cre-mediated deletion of Sox2. The expression of the transcription factor SIX6, known for its role in promoting cell proliferation, was downregulated. Conversely expression of the cell cycle inhibitor p27kip1 is up-regulated, in the absence of Sox2. Furthermore, the proliferation defect in Sox2 mutants can be rescued by homozygous loss of p27kip1, demonstrating a genetic interaction. This suggests that SOX2 promotes progenitor cell proliferation in the early RP and may do so, at least in part, by regulating Six6 and p27kip1 expression. Sox2 RP mutants display a disproportionate reduction in melanotroph cell numbers in the intermediate lobe (IL). The Sox2-deleted cells display a downregulation of the melanotroph lineage specifier, PAX7. Consequently, the few differentiated cells present in mutant IL switch from a melanotroph identity to a corticotroph fate, despite these cells never being present in the normal IL. This phenotype was not rescued in p27kip1;Sox2 compound mutants. This suggests that SOX2 plays two independent roles during pituitary development, initially promoting progenitor proliferation and later specifying IL melanotroph cell fate.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available