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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE142074 | GEO | 2020/02/26

REPOSITORIES: GEO

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

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

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Project description:Mutations in the pituitary specific transcription factor Prophet of Pit-1 (PROP1) are the most common genetic etiology of combined pituitary hormone deficiency (CPHD). CPHD is associated with short stature, attributable to growth hormone deficiency and/or thyroid stimulating hormone deficiency, as well as hypothyroidism and infertility. Pathogenic lesions impair pituitary development and differentiation of endocrine cells. We performed single-cell RNA sequencing of pituitary cells from a wild-type and a Prop1-mutant P4 female to elucidate population-specific differential gene expression. We observed a Smoc2+ve population that expressed low Sox2, which trajectory analyses suggest are a transitional cell state as stem cells differentiate into endocrine cells. We also detected ectopic expression of Sox21 in these cells in the Prop1df/df mutant. Prop1-mutant mice are known to overexpress Pou3f4, which we now show to be also enriched in this Smoc2+ve population. We sought to elucidate the role of Pou3f4 during pituitary development and to determine the contributions of Pou3f4 upregulation to pituitary disease by utilizing double-mutant mice lacking both Prop1 and Pou3f4. However, our data showed that Pou3f4 is not required for normal pituitary development and function. Double mutants further demonstrated that the upregulation of Pou3f4 was not causative for the overexpression of Sox21. These data indicate loss of Pou3f4 is not a potential cause of CPHD, and further studies may investigate the functional consequence of upregulation of Pou3f4 and Sox21, if any, in the novel Smoc2+ve cell population.

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Project description:Transcription factors and signaling pathways that regulate stem cells and specialized hormone-producing cells in the pituitary gland have been the subject of intense study and have yielded a mechanistic understanding of pituitary organogenesis and disease. Yet, the regulation of stem cell proliferation and differentiation, the heterogeneity among specialized hormone-producing cells, and the role of non-endocrine cells in the gland remain important, unanswered questions. Recent advances in single-cell RNA sequencing (scRNAseq) technologies provide new avenues to address these questions. We performed scRNAseq on approximately 13,663 cells pooled from six whole pituitary glands of 7-week-old C57BL/6 male mice. We identified pituitary endocrine and stem cells in silico, as well as other support cell-types such as endothelia, connective tissue, and red and white blood cells. Differential gene expression analyses identify known and novel markers of pituitary endocrine and stem cell populations. We demonstrate the value of scRNAseq by in vivo validation of a novel gonadotrope-enriched marker, Foxp2. We present novel scRNAseq data of in vivo pituitary tissue, including data from agnostic clustering algorithms which suggest the presence of a somatotrope subpopulation enriched in sterol/cholesterol synthesis genes. At the same time, we show that incomplete transcriptome annotation can cause false negatives on some scRNAseq platforms that only generate 3’ transcript end sequences, and use in vivo data to recover reads of the pituitary transcription factor Prop1. Ultimately, scRNAseq technologies represent a significant opportunity to address longstanding questions regarding the development and function of the different populations of the pituitary gland throughout life.

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Candidate Genes for Panhypopituitarism identified by gene expression profile

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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

ena-DATASET-2LF-23-03-2015-13:33:12:753-603 - samples

Project description:The dataset for the PROP1 study consists of samples of patients with combined pituitary hormone deficiency due to two most prevalent mutations in the PROP1 gene (c.301_302delGA and c.150delA) and healthy relatives and controls. All subjects were genotyped for 21 single nucleotide polymorphisms surrounding the PROP1 gene in order to assess the potential ancestral origin of the respective mutations. The genotype data are displayed in the vcf format.

| EGAD00001001303 | EGA

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