scholarly journals Control of the anterior pituitary cell lineage regulator POU1F1 by the stem cell determinant Musashi

Endocrinology ◽  
2020 ◽  
Author(s):  
Melody Allensworth-James ◽  
Jewel Banik ◽  
Angela Odle ◽  
Linda Hardy ◽  
Alex Lagasse ◽  
...  
Keyword(s):  
Stem Cell ◽  
Translational Control ◽  
Anterior Pituitary ◽  
Transcriptional Control ◽  
Mrna Translation ◽  
Stem Cell Marker ◽  
Pituitary Cells ◽  
Control Female ◽  
Leptin Signaling ◽  
Leptin Receptors

Abstract The adipokine leptin regulates energy homeostasis through ubiquitously expressed leptin receptors. Leptin has a number of major signaling targets in the brain, including cells of the anterior pituitary (AP). We have previously reported that mice lacking leptin receptors in AP somatotropes display growth hormone (GH) deficiency, metabolic dysfunction and adult onset obesity. Amongst other targets, leptin signaling promotes increased levels of the pituitary transcription factor POU1F1 which, in turn, regulates the specification of somatotrope, lactotrope and thyrotrope cell lineages within the AP. Leptin’s mechanism of action on somatotropes is sex-dependent, with females demonstrating post-transcriptional control of Pou1f1 mRNA translation. Here, we report that the stem cell marker and mRNA translational control protein, Musashi1, exerts repression of the Pou1f1 mRNA. In female somatotropes, Msi1 mRNA and protein levels are increased in the mouse model that lacks leptin signaling (Gh-CRE Lepr-null), coincident with lack of POU1f1 protein, despite normal levels of Pou1f1 mRNA. Single-cell RNA sequencing of pituitary cells from control female animals indicates that both Msi1 and Pou1f1 mRNAs are expressed in Gh-expressing somatotropes and immunocytochemistry confirms that Musashi1 protein is present in the somatotrope cell population. We demonstrate that Musashi interacts directly with the Pou1f1 mRNA 3’ untranslated region and exerts translational repression of a Pou1f1 mRNA translation reporter in a leptin-sensitive manner. Musashi immunoprecipitation from whole pituitary reveals co-associated Pou1f1 mRNA. These findings suggest a mechanism in which leptin stimulation is required to reverse Musashi-mediated Pou1f1 mRNA translational control to coordinate AP somatotrope function with metabolic status.

scholarly journals Transcriptomic heterogeneity of Sox2-expressing pituitary cells

2021 ◽  
Author(s):  
Patrick A. Fletcher ◽  
Rafael M. Prévide ◽  
Kosara Smiljanic ◽  
Arthur Sherman ◽  
Steven L. Coon ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Types ◽  
Stem Cell Marker ◽  
Marker Genes ◽  
Pituitary Cells ◽  
Posterior Lobe ◽  
Female Rat ◽  
Stem Cell Pluripotency ◽  
Cell Niche ◽  
Rat Pituitary Cells

AbstractThe mammalian pituitary gland is a complex organ consisting of hormone-producing cells (HPC), nonhormonal folliculostellate cells (FSC) and pituicytes, vascular pericytes and endothelial cells, and putative Sox2-expressing stem cells. Here, we used scRNAseq analysis of adult female rat pituitary cells to study the heterogeneity of pituitary cells with a focus on evaluating the transcriptomic profile of the Sox2-expressing population. Samples containing whole pituitary and separated anterior and posterior lobe cells allowed the identification of all expected pituitary resident cell types and lobe-specific subpopulations of vascular cells. Sox2 was expressed uniformly in all FSC, pituicytes, and a fraction of HPC. FSC comprised two subclusters; FSC1 contained more cells but expressed less genetic diversity compared to FSC2. The latter contained proliferative cells, expressed genes consistent with stem cell niche formation, including tight junctions, and shared genes with HPC. The FSC2 transcriptome profile was also consistent with the activity of pathways regulating cell proliferation and stem cell pluripotency, including the Hippo and Wnt pathways. The expression of other stem cell marker genes was common for FSC and pituicytes (Sox9, Cd9, Hes1, Vim, S100b) or cell type-specific (FSC: Prop1, Prrx1, Pitx1, Pitx2, Lhx3; pituicytes: Fgf10, Tbx3, Lhx2, Nkx2-1, Rax). FSC and pituicytes also expressed other astroglial marker genes, some common and other distinct, consistent with their identities as astroglial cells of the pituitary. These data suggest functional heterogeneity of FSC, with a larger fraction representing classical FSC, and a smaller fraction containing active stem-like cells and HPC-committed progenitors.

scholarly journals N1-acetylspermidine is a determinant of hair follicle stem cell fate

2021 ◽  
Vol 134 (9) ◽  
Author(s):  
Kira Allmeroth ◽  
Christine S. Kim ◽  
Andrea Annibal ◽  
Andromachi Pouikli ◽  
Janis Koester ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hair Follicle ◽  
Cell Fate ◽  
Translational Control ◽  
Mrna Translation ◽  
Stem Cell Differentiation ◽  
Stem Cell Fate ◽  
Cell Fate Decisions ◽  
Hair Follicle Stem Cell

ABSTRACT Stem cell differentiation is accompanied by increased mRNA translation. The rate of protein biosynthesis is influenced by the polyamines putrescine, spermidine and spermine, which are essential for cell growth and stem cell maintenance. However, the role of polyamines as endogenous effectors of stem cell fate and whether they act through translational control remains obscure. Here, we investigate the function of polyamines in stem cell fate decisions using hair follicle stem cell (HFSC) organoids. Compared to progenitor cells, HFSCs showed lower translation rates, correlating with reduced polyamine levels. Surprisingly, overall polyamine depletion decreased translation but did not affect cell fate. In contrast, specific depletion of natural polyamines mediated by spermidine/spermine N1-acetyltransferase (SSAT; also known as SAT1) activation did not reduce translation but enhanced stemness. These results suggest a translation-independent role of polyamines in cell fate regulation. Indeed, we identified N1-acetylspermidine as a determinant of cell fate that acted through increasing self-renewal, and observed elevated N1-acetylspermidine levels upon depilation-mediated HFSC proliferation and differentiation in vivo. Overall, this study delineates the diverse routes of polyamine metabolism-mediated regulation of stem cell fate decisions. This article has an associated First Person interview with the first author of the paper.

scholarly journals Leptin: A Metabolic Signal for the Differentiation of Pituitary Cells

2021 ◽  
Author(s):  
Gwen V. Childs ◽  
Angela K. Odle ◽  
Melanie C. MacNicol ◽  
Melody L. Allensworth-James ◽  
Tiffany K. Miles ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Cell Function ◽  
Regulatory Protein ◽  
Cell Types ◽  
Pituitary Cell ◽  
Pituitary Cells ◽  
Leptin Receptors ◽  
Metabolic States ◽  
Metabolic Signal ◽  
Post Transcriptional Regulation

Pituitary cell function is impacted by metabolic states and therefore must receive signals that inform them about nutritional status or adiposity. A primary signal from adipocytes is leptin, which recent studies have shown regulates most pituitary cell types. Subsets of all pituitary cell types express leptin receptors and leptin has been shown to exert transcriptional control through classical JAK/STAT pathways. Recent studies show that leptin also signals through post-transcriptional pathways that involve the translational regulatory protein Musashi. Mechanistically, post-transcriptional control would permit rapid cellular regulation of critical pre-existing pituitary transcripts as energy states change. The chapter will review evidence for transcriptional and/or post-transcriptional regulation of leptin targets (including Gnrhr, activin, Fshb, Gh, Ghrhr, and Pou11f1) and the consequences of the loss of leptin signaling to gonadotrope and somatotrope functions.

scholarly journals Organoids from pituitary as a novel research model toward pituitary stem cell exploration

2019 ◽  
Vol 240 (2) ◽  
pp. 287-308 ◽  
Author(s):  
Benoit Cox ◽  
Emma Laporte ◽  
Annelies Vennekens ◽  
Hiroto Kobayashi ◽  
Charlotte Nys ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Biology ◽  
Stem Cell Marker ◽  
Stem Cell Population ◽  
Endocrine Gland ◽  
Stem Cell Biology ◽  
Pituitary Cells ◽  
Research Model ◽  
Regulatory Pathways

The pituitary is the master endocrine gland, harboring stem cells of which the phenotype and role remain poorly characterized. Here, we established organoids from mouse pituitary with the aim to generate a novel research model to study pituitary stem cell biology. The organoids originated from the pituitary cells expressing the stem cell marker SOX2 were long-term expandable, displayed a stemness phenotype during expansive culture and showed specific hormonal differentiation ability, although limited, after subrenal transplantation. Application of the protocol to transgenically injured pituitary harboring an activated stem cell population, resulted in more numerous organoids. Intriguingly, these organoids presented with a cystic morphology, whereas the organoids from undamaged gland were predominantly dense and appeared more limited in expandability. Transcriptomic analysis revealed distinct epithelial phenotypes and showed that cystic organoids more resembled the pituitary phenotype, at least to an immature state, and displayed in vitro differentiation, although yet moderate. Organoid characterization further exposed facets of regulatory pathways of the putative stem cells of the pituitary and advanced new injury-activated markers. Taken together, we established a novel organoid research model revealing new insights into the identity and regulation of the putative pituitary stem cells. This organoid model may eventually lead to an interesting tool to decipher pituitary stem cell biology in both healthy and diseased gland.

scholarly journals SAT-284 Musashi Exerts Translational Control Within Anterior Pituitary Cells of the POU1F1 Lineage

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Melody Lyn Allensworth ◽  
Angela Katherine Odle ◽  
Ana Rita Silva Moreira ◽  
Juchan Lim ◽  
Jewel Banik ◽  
...  
Keyword(s):  
Cell Fate ◽  
Translational Control ◽  
In Silico Analysis ◽  
Regulatory Elements ◽  
Pituitary Cells ◽  
Control Male ◽  
Control Female ◽  
Protein Levels

Abstract The activation of transcription factor Pou1f1 at embryonic day 13 gives rise to the pituitary populations of somatotropes, lactotropes, and thyrotropes and these populations maintain expression of Pou1f1 throughout life. The Musashi family of RNA regulatory proteins is known to regulate stem cell fate by repressing translation of target mRNAs needed for differentiation. Previously our lab has shown that female Lepr-null somatotropes have reduced POU1F1 protein levels but do not have changes in Pou1f1 mRNA expression. Stimulation with leptin increased the POU1F1 protein levels 3-fold, but did not change Pou1f1 mRNA suggesting a post-transcriptional mechanism for leptin’s regulation of Pou1f1. An in silico analysis indicated the presence a number of potential regulatory elements (MBEs) within the Pou1f1 mRNA 3’ UTR, including 8 consensus Musashi binding elements. Interestingly, we found musashi mRNA and protein levels were increased in Lepr-null somatotropes. This suggested that leptin regulates the expression of musashi in somatotrope populations and may be a candidate translational regulator of the Pou1f1 mRNA. We verified that MSI binds directly to the Pou1f1 mRNA 3’ UTR MBEs by EMSA in vitro and exerts translational repression (using reporter mRNA assays in transfected cell populations). Single cell RNA sequencing of pituitary cells from control male and female mice indicates that MSI and Pou1f1 mRNAs are co-expressed in somatotropes, lactotropes as well as thyrotropes. Immunocytochemical analyses confirmed that Musashi protein is present in mixed and purified somatotrope populations. Furthermore, immunoprecipitation with Musashi1 antibody showed a 5-fold enrichment of Pou1f1 mRNA in control female mouse pituitaries. These findings point to a critical in vivo role for Musashi-mediated mRNA translational regulation within the Pou1f1 lineage and specifically in the control of somatotrope maturation and response to metabolic cues.

The Corneal Epithelial Stem Cell Marker - Novel Combination of High Expression of p63 and a Large N/C Ratio

2008 ◽  
Vol 1 (3) ◽  
pp. 95-105
Author(s):  
Arpitha P. ◽  
Prajna N. V. ◽  
Srinivasan M. ◽  
Muthukkaruppan V. R.
Keyword(s):  
Stem Cell ◽  
High Expression ◽  
Stem Cell Marker ◽  
Cell Marker ◽  
Corneal Epithelial ◽  
Epithelial Stem Cell ◽  
Large N
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