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 humansthat 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. IntroductionHeterozygous mutations in sex-determining region Y (SRY) box 2 (SOX2) have been associated with major eye abnormalities (i.e., anophthalmia, microphthalmia, and coloboma), hypopituitarism characterized by pituitary hypoplasia on imaging, and gonadotrophin deficiency (hypogonadotrophic hypogonadism [HH]) (1). In addition to hypoplasia of the corpus callosum, hypothalamic hamartoma, and hippocampal malformation, patients carrying inactivating SOX2 mutations frequently manifest other defects, such as esophageal atresia, sensorineural hearing loss, pituitary masses, and learning difficulties. Numerous nonsense, frameshift, and missense mutations, leading to the expression of SOX2 proteins with compromised function, as well as chromosomic deletions encompassing SOX2 have been identified (2).SOX2 is a member of the SRY-related HMG box B1 (SOXB1) subfamily of transcription factors, which also includes SOX1 and SOX3 (3). In both humans and mice, SOX2 is widely expressed during embryonic development throughout the entire epithelium of the brain and posterior neural tube, including the cortex, hippocampus, cerebellum, and spinal cord (4). In addition, persistent SOX2 expression is observed in the developing eye, in particular in the lens, neural retina, and optic nerve, and also in the prosensory region of the cochlea (5, 6). Endoderm-derived organ...

Transcription factor 7-like 1 is involved in hypothalamo–pituitary axis development in mice and humans

“…Hesx1 Cre/+ ;R26 loxP-YFP/+ 18.5 dpc embryos display widespread yellow fluorescent protein (YFP) expression in the vast majority of cells of the anterior pituitary, suggesting that the Hesx1-expressing RP progenitors give rise to all hormone-producing cells (Hesx1-cell lineage). In addition to RP, Hesx1 Cre/+ ;R26 loxP-YFP/+ and Hesx1 Cre/+ ;R26 loxP-lacZ/+ embryos show reporter expression in the ventral telencephalon and preoptic hypothalamic area from 9.5 dpc (49)(50)(51). Tcf7l1 is expressed in the forebrain, including the hypothalamic area, as well as in the anterior pituitary until 14.5 dpc (37).…”

“…Histological processing of embryos and in situ hybridization on paraffin sections was performed as previously described (53,54). The antisense riboprobes used in this study [Gh, glycoprotein hormone α (Cga), Pomc1, Prop1, Lh, Tsh, Fgf10, Fgf8, Bmp4, LIM homeobox protein 3 (Lhx3), Bmp4, T-box 2 (Tbx2), T-box 3 (Tbx3), and Pit1] have been described (51,(53)(54)(55). Human TCF7L1 riboprobe was generated using a full-length cDNA cloned into pCMV-Sport6 (SalI 5′, NotI 3′) (clone no.…”

“…Embryos were fixed in 4% (wt/vol) paraformaldehyde and processed for immunodetection as previously described (11,51). Detection of hormones was carried out using antibodies for (α-ACTH) (10C-CR1096M1), α-TSH (NHPP AFP-1274789), α-PRL (NHPP AFP-425-10-91), α-LH (NHPP AFP-C697071P), and α-FSH (AFP-7798-1289) (Developmental Studies Hybridoma Bank) at a 1:1,000 dilution.…”

Pituitary Stem Cells: Quest for Hidden Functions

“…Within the first group, the key stem-cell regulatory transcription factors SOX2 [SRY (sex determining region Y)-box 2] and SOX9 (Arnold et al 2011;Jayakody et al 2012;Pevny and Nicolis 2010) occupy a wellrecognized position. The SOX factors 'color' cells that reside in the marginal zone (MZ), which borders the cleft (Fig.…”

60 YEARS OF NEUROENDOCRINOLOGY: Biology of human craniopharyngioma: lessons from mouse models

“…RP contains the embryonic precursors of the pituitary gland that generate all of the hormone-producing cells of the anterior pituitary (Bilodeau et al 2009, Davis et al 2011, Jayakody et al 2012. Based on patterns of cytokeratin expression, it has been suggested that ACP may derive from remnants of RP epithelium in humans.…”