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SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice III

ABSTRACT: Exploration of the molecular mechanisms underlying melanotroph tumourigenesis and the role of SOX2 in both SCs and melanotrophs

ORGANISM(S): Mus musculus

PROVIDER: GSE152009 | GEO | 2021/02/24

REPOSITORIES: GEO

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SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-02-24 | GSE152010 | GEO

SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice II

Project description:Characterization of the effects of Sox2 heterozygosity on tumorigenesis in p27-/- pituitary tumors.

2021-02-24 | GSE152008 | GEO

SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice I

Project description:Characterization of the initiation and development of pituitary intermediate lobe tumors in p27-/- mice.

2021-02-24 | GSE152007 | GEO

SOX2 is required independently in both stem and differentiated cells for pituitary tumorigenesis in <i>p27</i>-null mice.

Project description:P27, a cell cycle inhibitor, is also able to drive repression of Sox2 This interaction plays a crucial role during development of p27-/- pituitary tumors because loss of one copy of Sox2 impairs tumorigenesis [H. Li et al., Cell Stem Cell 11, 845-852 (2012)]. However, SOX2 is expressed in both endocrine and stem cells (SCs), and its contribution to tumorigenesis in either cell type is unknown. We have thus explored the cellular origin and mechanisms underlying endocrine tumorigenesis in p27-/- pituitaries. We found that pituitary hyperplasia is associated with reduced cellular differentiation, in parallel with increased levels of SOX2 in stem and endocrine cells. Using conditional loss-of-function and lineage tracing approaches, we show that SOX2 is required cell autonomously in p27-/- endocrine cells for these to give rise to tumors, and in SCs for promotion of tumorigenesis. This is supported by studies deleting the Sox2 regulatory region 2 (Srr2), the target of P27 repressive action. Single cell transcriptomic analysis further reveals that activation of a SOX2-dependent MAPK pathway in SCs is important for tumorigenesis. Altogether, our data highlight different aspects of the role of SOX2 following loss of p27, according to cellular context, and uncover an unexpected SOX2-dependent tumor-promoting role for SCs. Our results imply that targeting SCs, in addition to tumor cells, may represent an efficient antitumoral strategy in certain contexts.

| S-EPMC7896314 | biostudies-literature

SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice III

Project description:SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice III

| PRJNA638094 | ENA

SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice

Project description:SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice

| PRJNA638090 | ENA

SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice I

Project description:SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice I

| PRJNA638092 | ENA

SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice II

Project description:SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice II

| PRJNA638093 | ENA

p27(Kip1) directly represses Sox2 during embryonic stem cell differentiation.

Project description:The mechanisms responsible for the transcriptional silencing of pluripotency genes in differentiated cells are poorly understood. We have observed that cells lacking the tumor suppressor p27 can be reprogrammed into induced pluripotent stem cells (iPSCs) in the absence of ectopic Sox2. Interestingly, cells and tissues from p27 null mice, including brain, lung, and retina, present an elevated basal expression of Sox2, suggesting that p27 contributes to the repression of Sox2. Furthermore, p27 null iPSCs fail to fully repress Sox2 upon differentiation. Mechanistically, we have found that upon differentiation p27 associates to the SRR2 enhancer of the Sox2 gene together with a p130-E2F4-SIN3A repressive complex. Finally, Sox2 haploinsufficiency genetically rescues some of the phenotypes characteristic of p27 null mice, including gigantism, pituitary hyperplasia, pituitary tumors, and retinal defects. Collectively, these results demonstrate an unprecedented connection between p27 and Sox2 relevant for reprogramming and cancer and for understanding human pathologies associated with p27 germline mutations.

| S-EPMC3549496 | biostudies-literature

SOX2 regulates the hypothalamic-pituitary axis at multiple levels.

Project description: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.

| S-EPMC3461924 | biostudies-literature

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