Interactions between pituitary cell lineages direct tissue architecture and size
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE227561 | GEO | 2024/09/30
REPOSITORIES: GEO
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Project description:Pituitary gland function is regulated by the activity of various transcription factors which control cell fate decisions leading to cellular differentiation and hormone production. FOXO1 is necessary for the proper timing of somatotrope differentiation and for somatotrope function, but the exact mechanism of action has yet to be elucidated. Recent data implicate FOXO1 in the regulation of genes important for somatotrope differentiation including Gh1, Neurod4, and Pou1f1. Previously, a mouse model with conditional deletion of Foxo1 from the developing pituitary gland displayed reduced Gh1 and Neurod4 transcripts as early as embryonic day 18.5. Additional data from adult animals with conditional deletion of both Foxo1 and Foxo3 from the pituitary gland have a similar reduction in Neurod4 and Gh1, as well as Pou1f1. To investigate the mechanism by which FOXO1 regulates pituitary gland gene expression and confirm in vivo findings, the somatotrope-like cell line, GH3, was treated with the FOXO1 inhibitor, AS1842856, for 24 hours at various concentrations. Neurod4 was the most severely affected genes with a dose-dependent reduction in transcript at inhibitor concentrations as low as 30 nM. Gh1 transcripts were significantly reduced at 300 nM. Pou1f1 expression was trending down at 3 microM inhibitor (p=0.066). Consistent with these findings, CRISPR/Cas9-mediated deletion of Foxo1 in GH3 cells significantly reduced expression of Gh1, Neurod4, but not Pou1f1. To elucidate the molecular mechanisms underlying the role of FOXO1 in somatotropes, ChIPseq was performed for FOXO1 in the GH3 cell line. This study identified novel FOXO1 binding sites associated with the Neurod4, Gh1, and Pou1f1 genes. The FOXO1 binding site in the Neurod4 gene exhibits enhancer activity in somatotrope-like cells, but not in gonadotrope-like or heterologous cells. These data strongly suggest FOXO1 directly contributes to the transcriptional control of genes important for somatotrope differentiation. These novel findings contribute to the much-needed understanding of pituitary cell fate decisions.
2023-12-14 | GSE245740 | GEO
Project description:The differentiation of the hormone-producing cell lineages of the anterior pituitary represents an informative model of mammalian cell fate determination. The generation and maintenance of two of these lineages, the growth hormone (GH) producing somatotropes and prolactin (PRL) producing lactotropes, is dependent on the pituitary-specific POU-homeo domain transcription factor, POU1F1. While POU1F1 is expressed in both cell types, and plays a direct and essential role in the activation of both the Gh and Prl genes, GH expression is restricted to somatotropes and PRL expression is restricted to lactotropes. These observations imply the existence of additional, cell type-enriched factors, that contribute to the somatotrope and lactotrope cell identities. Here, we use a set of transgenic mouse models to facilitate sorting of somatotrope and lactotrope populations based on the expression of distinct fluorescent markers expressed under Gh and Prl gene transcriptional controls, respectively. The transcriptomic analyses reveal a concordance of gene expression profiles in the two populations. The limited number of divergent mRNAs between the two populations includes a set of transcription factors that may have roles in pituitary lineage divergence or in regulating the expression of key lineage-specific genes after lineage divergence. Four of these factors were validated for lineage enrichment at the level of protein expression, two somatotrope-enriched and two lactotrope-enriched, and three of these four factors were shown to have corresponding activities in appropriate enhancement or repression of landmark genes. These studies establish a useful database for further study of the somatotrope and lactotrope cells as well as identify novel regulators of lineage marker expression in the anterior pituitary.
2018-10-31 | GSE118863 | GEO
Project description:Pituitary neuroendocrine tumors (PitNETs) account for the second most common intracranial tumors. Currently, there is still a lack of comprehensive understanding regarding the molecular mechanisms associated with lineage or clinical features of PitNETs, which hinders development of effective treatment strategies. Herein, we performed in-depth proteome profiling of 68 PitNET tumors and 4 pituitary glands. We systematically investigated the common and specific aberrant biological mechanisms in TPIT (ACTH/SCA) and PIT1 (TSH/PRL/GH) lineages. Our findings revealed that Wnt signaling pathway and MAPK signaling pathway played crucial regulatory roles in both lineages, while lipid metabolism abnormalities were more prominent in TPIT lineage, and decreased cell adhesion was more significant in PIT1 lineage. Based on these findings, we delved into the interactions between drugs and proteins to explore reliable drug targets and treatment options. We identified 17 potential drug targets and 51 FDA-approved drugs in TPIT lineage, and 19 potential drug targets and 97 FDA-approved drugs in PIT1 lineage, respectively. Additionally, we reclassified the samples based on 4 important clinical phenotypes: invasiveness, recurrence, high incidence in women of childbearing age, and tumor stiffness. By combining artificial intelligence (AI) and bioinformatics analysis, we further investigated the related mechanistic information. Our results highlighted the close association of abnormal neuronal activity with tumor invasiveness, as well as the intimate correlation between cell adhesion alterations and the other 3 clinical phenotypes. Overall, our study provides valuable insights into both of lineage-based and clinical feature-based pathophysiological mechanisms of PitNETs, and offers novel reference for future targeted therapies.
2023-12-17 | PXD047883 | iProX
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.
2018-10-19 | GSE120410 | GEO
Project description:Corticotropin (ACTH)-secreting pituitary adenomas give rise to a severe endocrinological disorder, i.e., Cushing’s disease, with multifaceted clinical presentation and treatment outcomes. Experimental studies suggested that disease variability is inherent to the pituitary tumor, thus pointing to the need for further studies into tumor biology. Aim of the present study was to evaluate transcriptome expression pattern in a large series of ACTH-secreting pituitary adenoma specimens, in order to identify molecular signatures of these tumors. Gene expression profiling of formalin-fixed paraffin-embedded specimens from 40 human ACTH-secreting pituitary adenomas revealed significant expression of genes involved in protein biosynthesis and ribosomal function, in keeping with neuroendocrine cell profile. Unsupervised cluster analysis identified three distinct gene profile clusters and several genes were uniquely overexpressed in a given cluster, accounting for different molecular signatures. Of note, gene expression profiles were associated with clinical features such as age and size of the tumor. Altogether, our study shows that corticotrope tumors are characterized by neuroendocrine gene expression profile and present subgroup-specific molecular features.
2018-06-18 | GSE93825 | GEO
Project description:Translation is a basic cellular process and its capacity is adapted to cell function. In particular, secretory cells achieve high protein synthesis levels without triggering the protein stress response. It is unknown how and when translation capacity is increased during differentiation. Here, we show that the transcription factor Creb3l2 is a scaling factor for translation capacity in pituitary secretory cells and that it directly binds ~75% of regulatory and effector genes for translation. In parallel with this cell-autonomous mechanism, implementation of the physiological UPR pathway prevents triggering the protein stress response. The pituitary differentiation factor Tpit activates Creb3l2 expression, the Creb3l2-dependent regulatory network as well as the physiological UPR pathway. Thus, Creb3l2 implements high basal translation levels through direct targeting of translation effector genes acting downstream of signaling pathways that otherwise regulate protein synthesis. Expression of Creb3l2 may be a useful means to enhance production of therapeutic proteins.
2019-07-29 | GSE132322 | GEO
Project description:Translation is a basic cellular process and its capacity is adapted to cell function. In particular, secretory cells achieve high protein synthesis levels without triggering the protein stress response. It is unknown how and when translation capacity is increased during differentiation. Here, we show that the transcription factor Creb3l2 is a scaling factor for translation capacity in pituitary secretory cells and that it directly binds ~75% of regulatory and effector genes for translation. In parallel with this cell-autonomous mechanism, implementation of the physiological UPR pathway prevents triggering the protein stress response. The pituitary differentiation factor Tpit activates Creb3l2 expression, the Creb3l2-dependent regulatory network as well as the physiological UPR pathway. Thus, Creb3l2 implements high basal translation levels through direct targeting of translation effector genes acting downstream of signaling pathways that otherwise regulate protein synthesis. Expression of Creb3l2 may be a useful means to enhance production of therapeutic proteins.
2019-07-29 | GSE132321 | GEO
Project description:Translation is a basic cellular process and its capacity is adapted to cell function. In particular, secretory cells achieve high protein synthesis levels without triggering the protein stress response. It is unknown how and when translation capacity is increased during differentiation. Here, we show that the transcription factor Creb3l2 is a scaling factor for translation capacity in pituitary secretory cells and that it directly binds ~75% of regulatory and effector genes for translation. In parallel with this cell-autonomous mechanism, implementation of the physiological UPR pathway prevents triggering the protein stress response. The pituitary differentiation factor Tpit activates Creb3l2 expression, the Creb3l2-dependent regulatory network as well as the physiological UPR pathway. Thus, Creb3l2 implements high basal translation levels through direct targeting of translation effector genes acting downstream of signaling pathways that otherwise regulate protein synthesis. Expression of Creb3l2 may be a useful means to enhance production of therapeutic proteins.
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Project description:Pioneer transcription factors are coined as having the unique property of “opening closed chromatin sites” for implementation of cell fates. We previously showed that the pioneer Pax7 specifies melanotrope cells through deployment of an enhancer repertoire: this allows binding of Tpit, a nonpioneer factor that determines the related lineages of melanotropes and corticotropes. Here, we investigated the relation between these two factors in the pioneer mechanism. Cell-specific gene expression and chromatin landscapes were defined by scRNAseq and chromatin accessibility profiling. We found that in vivo deployment of the melanotrope enhancer repertoire and chromatin opening requires both Pax7 and Tpit. In cells, binding of heterochromatin targets by Pax7 is independent of Tpit but Pax7-dependent chromatin opening requires Tpit. The present work shows that pioneer core properties are limited to the ability to recognize heterochromatin targets and facilitate nonpioneer binding. Chromatin opening per se may be provided through cooperation with nonpioneer factors.
2019-07-29 | GSE125670 | GEO
Project description:Pioneer transcription factors are coined as having the unique property of “opening closed chromatin sites” for implementation of cell fates. We previously showed that the pioneer Pax7 specifies melanotrope cells through deployment of an enhancer repertoire: this allows binding of Tpit, a nonpioneer factor that determines the related lineages of melanotropes and corticotropes. Here, we investigated the relation between these two factors in the pioneer mechanism. Cell-specific gene expression and chromatin landscapes were defined by scRNAseq and chromatin accessibility profiling. We found that in vivo deployment of the melanotrope enhancer repertoire and chromatin opening requires both Pax7 and Tpit. In cells, binding of heterochromatin targets by Pax7 is independent of Tpit but Pax7-dependent chromatin opening requires Tpit. The present work shows that pioneer core properties are limited to the ability to recognize heterochromatin targets and facilitate nonpioneer binding. Chromatin opening per se may be provided through cooperation with nonpioneer factors.
2019-07-29 | GSE125668 | GEO