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PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells [ChIP-Seq]

ABSTRACT: Mutations in PROP1 are the most common cause of hypopituitarism in humans; therefore, unraveling its mechanism of action is highly relevant from a therapeutic perspective. Our current understanding of the role of PROP1 in the pituitary gland is limited to the regulation of pituitary transcription factors Hesx1 and Pit1. To elucidate the comprehensive PROP1-dependent gene regulatory network, we conducted genome wide analysis of PROP1 DNA binding and effects on gene expression in mutant tissues, isolated stem cells and engineered cell lines. We determined that PROP1 is essential for maintaining proliferation of stem cells and stimulating them to undergo an epithelial to mesenchymal transition-like process necessary for cell migration and differentiation. Genomic profiling reveals that PROP1 binds to and represses claudin 23, characteristic of epithelial cells, and it activates EMT inducer genes: Zeb2, Notch2 and Gli2. Our findings identify PROP1 as a central transcriptional component of pituitary stem cell differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE77302 | GEO | 2016/07/11

SECONDARY ACCESSION(S): PRJNA309997

REPOSITORIES: GEO

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PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells [RNA-Seq]

Project description:Mutations in PROP1 are the most common cause of hypopituitarism in humans; therefore, unraveling its mechanism of action is highly relevant from a therapeutic perspective. Our current understanding of the role of PROP1 in the pituitary gland is limited to the regulation of pituitary transcription factors Hesx1 and Pit1. To elucidate the comprehensive PROP1-dependent gene regulatory network, we conducted genome wide analysis of PROP1 DNA binding and effects on gene expression in mutant tissues, isolated stem cells and engineered cell lines. We determined that PROP1 is essential for maintaining proliferation of stem cells and stimulating them to undergo an epithelial to mesenchymal transition-like process necessary for cell migration and differentiation. Genomic profiling reveals that PROP1 binds to and represses claudin 23, characteristic of epithelial cells, and it activates EMT inducer genes: Zeb2, Notch2 and Gli2. Our findings identify PROP1 as a central transcriptional component of pituitary stem cell differentiation.

2016-07-11 | GSE77357 | GEO

Candidate Genes for Panhypopituitarism identified by gene expression profile

2011-12-14 | GSE30863 | GEO

Candidate Genes for Panhypopituitarism identified by gene expression profile

Project description:Prop1 controls the expression of genes besides Pit1 that are important for cell mgration, survival and differentiation in the mouse and human pituitary gland. Microarray analysis was used to compare pituitary RNA from newborn Prop1 and Pit1 mutants and their wild type littermates. Total RNA was collected and pooled from Prop1df/df, Porp1+/+, Pit1dw/dw, and Pit+/+ at the age of P1. 5 pools per genotype were hybridized to the Affymetrix Mouse Genome 430 2.0 array.

2011-12-14 | E-GEOD-30863 | biostudies-arrayexpress

PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells

Project description:PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells

| PRJNA310148 | ENA

PROP1-Dependent Retinoic Acid Signaling Regulates Developmental Pituitary Morphogenesis and Hormone Expression

Project description:Dietary vitamin A is metabolized into bioactive retinoic acid in vivo and regulates the development of many embryonic tissues. Retinoic acid signaling is active in the oral ectoderm-derived tissues of the neuroendocrine system, but its role there has not yet been fully explored. We show here that retinoic acid signaling is active during pituitary organogenesis and dependent on the pituitary transcription factor Prop1. Prop1-mutant mice show reduced expression of the aldehyde dehydrogenase gene Aldh1a2, which metabolizes the vitamin A-intermediate retinaldehyde into retinoic acid. In order to elucidate the specific function of RA signaling during neuroendocrine development, we studied a conditional deletion of Aldh1a2 and a dominant-negative mouse model of inhibited retinoic acid signaling during pituitary organogenesis. These models partially phenocopy Prop1-mutant mice by exhibiting embryonic pituitary dysmorphology and reduced hormone expression, especially of thyroid-stimulating hormone. These findings establish the critical role of retinoic acid in embryonic pituitary stem cell progression to differentiated hormone cells and raise the question of gene-by-environment interactions as contributors to pituitary development and disease.

2020-02-26 | GSE142074 | GEO

Gene expression analysis of FACS-isolated mammary stromal cells (Fsp1-expressing) between stromal Gli2 wild type control and stromal Gli2 ablated mice

Project description:The capacity of stem cells to maintain and regenerate organs is critically dependent on the niche, a complex signaling microenvironment that sustains and regulates stem cell activity. Niche function in the mammary gland must integrate local homeostatic activities with hormonally regulated events, such as pregnancy or the onset of puberty. In the human disorder CPHD (combined pituitary hormone deficiency) breast growth defects at puberty are associated with mutations disrupting the transcription factor, GLI2. Here we find that Gli2 functions in mouse mammary stromal cells to shape a niche signaling program that sustains mammary epithelial stem cells. Ablation of Gli2 in stromal cells thus leads to a disorganized mammary gland, associated with collapse of the niche signaling environment, with a five-fold decrease in functional mammary stem cell activity, and with attenuated response to the mammatrophic hormones estrogen and growth hormone. Consistent with a niche defect, aspects of Gli2-deficient mammary gland architecture can be rescued by local supplementation with IGF and WNT protein signals. Our findings thus identify GLI2 as a critical coordinator of local and hormonal influences on the niche signaling program, and suggest that mammary pathogenesis in CPHD patients results from dysfunction of the mammary epithelial stem cell niche. We used microarrays to identify gene expression signatures associated with stromal Gli2 expression

2015-03-13 | GSE66820 | GEO

Mus musculus

Project description:PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells [RNA-Seq]

| PRJNA310130 | ENA

Mus musculus

Project description:PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells [ChIP-Seq]

| PRJNA309997 | ENA

Rathke’s Cleft-Like Cysts Arise From Isl1 Deletion in Murine Pituitary Progenitors

Project description:The transcription factor ISL1 is expressed in pituitary gland stem cells and the thyrotrope and gonadotrope lineages. Pituitary-specific Isl1 deletion causes hypopituitarism with increased stem cell apoptosis, reduced differentiation of thyrotropes and gonadotropes, and reduced body size. Conditional Isl1 deletion causes development of multiple Rathke’s cleft-like cysts, with 100% penetrance. Foxa1 and Foxj1 are abnormally expressed in the pituitary gland and associated with a ciliogenic gene expression program in the cysts. We confirmed expression of FOXA1, FOXJ1 and stem cell markers in human Rathke's cleft cyst tissue, but not craniopharyngiomas, which suggests these transcription factors are useful, pathological markers for diagnosis of Rathke's cleft cysts. These studies support a model whereby expression of ISL1 in pituitary progenitors drives differentiation into thyrotropes and gonadotropes, and without it, activation of FOXA1 and FOXJ1 permits development of an oral epithelial cell fate with mucinous cysts. This pituitary-specific Isl1 mouse knockout sheds light on the etiology of Rathke's cleft cysts and the role of ISL1 in normal pituitary development.

2020-04-22 | GSE149019 | GEO

Multilineage pituitary neuroendocrine tumors with PIT1/SF1 co-expression

Project description:Pituitary neuroendocrine tumors (PitNET)/adenomas are classified according to cell lineage, which requires immunohistochemistry for the transcription factors (TFs) PIT1, SF1, and TPIT. Co-expression of PIT1/SF1 was previously reported in PitNETs, which otherwise correspond to the somatotroph lineage. However, little is known about the clinicopathological features of these tumors. We compiled an in-house case series of 100 tumors, previously diagnosed as densely or sparsely granulated somatotroph PitNETs. Following TF staining, histopathological features associated with PIT1/SF1-coexpression were assessed. Global DNA methylation profiling was conducted on 31 of 100 in-house samples and integrated with publicly available sample data. The majority (74%, 52/70) of our densely granulated somatotroph PitNETs (DGST) unequivocally co-expressed PIT1 and SF1 (DGST-PIT1/SF1). None of our SGST (0%, 0/30) stained positive for SF1 (SGST-PIT1). Integrated molecular analyses including publicly available sample data confirmed that DGST-PIT1/SF1, DGST-PIT1 and SGST-PIT1 represent distinct tumour subtypes. In summary, we spotlight that a substantial proportion of previously diagnosed densely granulated somatotroph PitNET co-express PIT1 and SF1 and exhibit clinical, histopathological, and molecular distinctness from other pure PIT1-lineage somatotroph PitNET.

2024-01-24 | GSE246645 | GEO

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