SOX2 regulates the hypothalamic-pituitary axis at multiple levels
Sujatha A. Jayakody, … , Mehul T. Dattani, Juan P. Martinez-Barbera
Sujatha A. Jayakody, … , Mehul T. Dattani, Juan P. Martinez-Barbera
Published September 4, 2012
Citation Information: J Clin Invest. 2012;122(10):3635-3646. https://doi.org/10.1172/JCI64311.
View: Text | PDF
Research Article Development

SOX2 regulates the hypothalamic-pituitary axis at multiple levels

Abstract

Sex-determining region Y (SRY) box 2 (SOX2) haploinsufficiency causes a form of hypopituitarism in humans that is characterized by gonadotrophin deficiency known as hypogonadotrophic hypogonadism. Here, we conditionally deleted Sox2 in mice to investigate the pathogenesis of hypogonadotrophic hypogonadism. First, we found that absence of SOX2 in the developing Rathke pouch of conditional embryos led to severe anterior lobe hypoplasia with drastically reduced expression of the pituitary-specific transcription factor POU class 1 homeobox 1 (POU1F1) as well as severe disruption of somatotroph and thyrotroph differentiation. In contrast, corticotrophs, rostral-tip POU1F1-independent thyrotrophs, and, interestingly, lactotrophs and gonadotrophs were less affected. Second, we identified a requirement for SOX2 in normal proliferation of periluminal progenitors; in its absence, insufficient precursors were available to produce all cell lineages of the anterior pituitary. Differentiated cells derived from precursors exiting cell cycle at early stages, including corticotrophs, rostral-tip thyrotrophs, and gonadotrophs, were generated, while hormone-producing cells originating from late-born precursors, such as somatotrophs and POU1F1-dependent thyrotrophs, were severely reduced. Finally, we found that 2 previously characterized patients with SOX2 haploinsufficiency and associated hypogonadotrophic hypogonadism had a measurable response to gonadotropin-releasing hormone (GnRH) stimulation, suggesting that it is not the absence of gonadotroph differentiation, but rather the deficient hypothalamic stimulation of gonadotrophs, that underlies typical hypogonadotrophic hypogonadism.

Authors

Sujatha A. Jayakody, Cynthia L. Andoniadou, Carles Gaston-Massuet, Massimo Signore, Anna Cariboni, Pierre M. Bouloux, Paul Le Tissier, Larysa H. Pevny, Mehul T. Dattani, Juan P. Martinez-Barbera

×

Figure 1

Abnormal pituitary morphogenesis and severe anterior lobe hypoplasia in Hesx1Cre/+;Sox2fl/fl mutant mice.

Options: View larger image (or click on image) Download as PowerPoint
Abnormal pituitary morphogenesis and severe anterior lobe hypoplasia in ...
H&E staining of sagittal (A–F) or transverse (G–I) histological sections from Hesx1Cre/+;Sox2fl/+ control and Hesx1Cre/+;Sox2fl/fl mutant embryos. (A and B) No significant differences in the morphology of RP and ventral diencephalon (VD) are observed between genotypes at 9.5 dpc. (C and D) By 12.5 dpc, the infundibulum (Inf), a depression of the floor of the ventral diencephalon, RP periluminal epithelium, and the developing AP are clearly distinguishable in a control embryo (C). However, RP and developing AP are dysmorphic and slightly hypoplastic in the mutant embryo (D). (E and F) At 14.5 dpc, a substantial AP has developed over the basisphenoid (BS) bone in the control embryo (E), but AP is dysmorphic, small, and ectopically located between the developing unfused basisphenoid cartilages in the mutant pituitary (F). (G–I) At 18.5 dpc, the pituitary gland is situated between the hypothalamus (Hypo) and basisphenoid and comprises the posterior, intermediate, and anterior lobes (PL, IL, and AL, respectively) in a control embryo (G). In the mutant pituitary, posterior lobes and intermediate lobes are morphologically distinguishable, but only a rudiment of the anterior lobe is observed, often lying between the unfused basisphenoid and in contact with the oropharyngeal cavity (OR). H and I show sections at different axial levels of the same embryo. Scale bars: 100 μm.