title: 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.affiliation: Neural Development Unit, Institute of Child Health, and Department of Cell and Developmental Biology, University College London, London, United Kingdom.
authors.forename: Sujatha A
authors.initials: SA
authors.lastname: Jayakody
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Andoniadou
authors.forename: Carles
authors.initials: C
authors.lastname: Gaston-Massuet
authors.forename: Massimo
authors.initials: M
authors.lastname: Signore
authors.forename: Anna
authors.initials: A
authors.lastname: Cariboni
authors.forename: Pierre M
authors.initials: PM
authors.lastname: Bouloux
authors.forename: Paul
authors.initials: P
authors.lastname: Le Tissier
authors.forename: Larysa H
authors.initials: LH
authors.lastname: Pevny
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
authors.forename: Juan P
authors.initials: JP
authors.lastname: Martinez-Barbera
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007987:Gonadotropin-Releasing Hormone / Q000627:therapeutic use; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007006:Hypogonadism / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D038081:Organogenesis / Q000235:genetics / Q000502:physiology; D010903:Pituitary Gland, Anterior / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D052683:Somatotrophs / Q000473:pathology; D052684:Thyrotrophs / Q000473:pathology; D050817:Transcription Factor Pit-1 / Q000172:deficiency
chemical_list: D007987:Gonadotropin-Releasing Hormone; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D055748:SOXB1 Transcription Factors; D050817:Transcription Factor Pit-1; C489733:Hesx1 protein, mouse; C494185:Pou1f1 protein, mouse; C527782:SOX2 protein, human; C527783:Sox2 protein, mouse