36 results on '"MacNicol, Melanie"'
Search Results
2. Single and double modified salinomycin analogs target stem-like cells in 2D and 3D breast cancer models
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Urbaniak, Alicja, Reed, Megan R., Fil, Daniel, Moorjani, Anika, Heflin, Sarah, Antoszczak, Michał, Sulik, Michał, Huczyński, Adam, Kupsik, Michalina, Eoff, Robert L., MacNicol, Melanie C., Chambers, Timothy C., and MacNicol, Angus M.
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- 2021
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3. Anterior Pituitary Transcriptomics Following a High-Fat Diet: Impact of Oxidative Stress on Cell Metabolism.
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Miles, Tiffany K, Odle, Angela K, Byrum, Stephanie D, Lagasse, Alex, Haney, Anessa, Ortega, Victoria G, Bolen, Cole R, Banik, Jewel, Reddick, Milla M, Herdman, Ashley, MacNicol, Melanie C, MacNicol, Angus M, and Childs, Gwen V
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PITUITARY cancer ,OXIDATIVE stress ,CELL metabolism - Abstract
Anterior pituitary cell function requires a high level of protein synthesis and secretion which depend heavily on mitochondrial adenosine triphosphate production and functional endoplasmic reticula. Obesity adds stress to tissues, requiring them to adapt to inflammation and oxidative stress, and adding to their allostatic load. We hypothesized that pituitary function is vulnerable to the stress of obesity. Here, we utilized a 10- to 15-week high-fat diet (HFD, 60%) in a thermoneutral environment to promote obesity, testing both male and female FVB.129P mice. We quantified serum hormones and cytokines, characterized the metabolic phenotype, and defined changes in the pituitary transcriptome using single-cell RNA-sequencing analysis. Weight gain was significant by 3 weeks in HFD mice, and by 10 weeks all HFD groups had gained 20 g. HFD females (15 weeks) had increased energy expenditure and decreased activity. All HFD groups showed increases in serum leptin and decreases in adiponectin. HFD caused increased inflammatory markers: interleukin-6, resistin, monocyte chemoattractant protein-1, and tumor necrosis factorα. HFD males and females also had increased insulin and increased TSH, and HFD females had decreased serum prolactin and growth hormone pulse amplitude. Pituitary single-cell transcriptomics revealed modest or no changes in pituitary cell gene expression from HFD males after 10 or 15 weeks or from HFD females after 10 weeks. However, HFD females (15 weeks) showed significant numbers of differentially expressed genes in lactotropes and pituitary stem cells. Collectively, these studies reveal that pituitary cells from males appear to be more resilient to the oxidative stress of obesity than females and identify the most vulnerable pituitary cell populations in females. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Maternal undernutrition results in transcript changes in male offspring that may promote resistance to high fat diet induced weight gain.
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Miles, Tiffany K., Allensworth-James, Melody L., Odle, Angela K., Moreira, Ana Rita Silva, Haney, Anessa C., LaGasse, Alex N., Gies, Allen J., Byrum, Stephanie D., Riojas, Angelica M., MacNicol, Melanie C., MacNicol, Angus M., and Childs, Gwen V.
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WEIGHT gain ,HIGH-fat diet ,NON-alcoholic fatty liver disease ,MATERNAL nutrition ,EMBRYOLOGY ,MALNUTRITION ,LOW-calorie diet - Abstract
Maternal nutrition during embryonic development and lactation influences multiple aspects of offspring health. Using mice, this study investigates the effects of maternal caloric restriction (CR) during mid-gestation and lactation on offspring neonatal development and on adult metabolic function when challenged by a high fat diet (HFD). The CR maternal model produced male and female offspring that were significantly smaller, in terms of weight and length, and females had delayed puberty. Adult offspring born to CR dams had a sexually dimorphic response to the high fat diet. Compared to offspring of maternal control dams, adult female, but not male, CR offspring gained more weight in response to high fat diet at 10 weeks. In adipose tissue of male HFD offspring, maternal undernutrition resulted in blunted expression of genes associated with weight gain and increased expression of genes that protect against weight gain. Regardless of maternal nutrition status, HFD male offspring showed increased expression of genes associated with progression toward nonalcoholic fatty liver disease (NAFLD). Furthermore, we observed significant, sexually dimorphic differences in serum TSH. These data reveal tissue- and sex-specific changes in gene and hormone regulation following mild maternal undernutrition, which may offer protection against diet induced weight gain in adult male offspring. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Musashi Exerts Control of Gonadotrope Target mRNA Translation During the Mouse Estrous Cycle.
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Moreira, Ana Rita Silva, Lim, Juchan, Urbaniak, Alicja, Banik, Jewel, Bronson, Katherine, Lagasse, Alex, Hardy, Linda, Haney, Anessa, Allensworth, Melody, Miles, Tiffany K, Gies, Allen, Byrum, Stephanie D, Wilczynska, Ania, Boehm, Ulrich, Kharas, Michael, Lengner, Christopher, MacNicol, Melanie C, Childs, Gwen V, MacNicol, Angus M, and Odle, Angela K
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MESSENGER RNA ,ESTRUS ,CARRIER proteins - Abstract
The anterior pituitary controls key biological processes, including growth, metabolism, reproduction, and stress responses through distinct cell types that each secrete specific hormones. The anterior pituitary cells show a remarkable level of cell type plasticity that mediates the shifts in hormone-producing cell populations that are required to meet organismal needs. The molecular mechanisms underlying pituitary cell plasticity are not well understood. Recent work has implicated the pituitary stem cell populations and specifically, the mRNA binding proteins of the Musashi family in control of pituitary cell type identity. In this study we have identified the target mRNAs that mediate Musashi function in the adult mouse pituitary and demonstrate the requirement for Musashi function in vivo. Using Musashi RNA immunoprecipitation, we identify a cohort of 1184 mRNAs that show specific Musashi binding. Identified Musashi targets include the Gnrhr mRNA, which encodes the gonadotropin-releasing hormone receptor (GnRHR), and the Fshb mRNA, encoding follicle-stimulating hormone (FSH). Reporter assays reveal that Musashi functions to exert repression of translation of the Fshb mRNA, in addition to the previously observed repression of the Gnrhr mRNA. Importantly, mice engineered to lack Musashi in gonadotropes demonstrate a failure to repress translation of the endogenous Gnrhr and Fshb mRNAs during the estrous cycle and display a significant heterogeneity in litter sizes. The range of identified target mRNAs suggests that, in addition to these key gonadotrope proteins, Musashi may exert broad regulatory control over the pituitary proteome in a cell type–specific manner. [ABSTRACT FROM AUTHOR]
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- 2023
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6. Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease
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Fil, Daniel, DeLoach, Abigail, Yadav, Shilpi, Alkam, Duah, MacNicol, Melanie, Singh, Awantika, Compadre, Cesar M., Goellner, Joseph J., O’Brien, Charles A., Fahmi, Tariq, Basnakian, Alexei G., Calingasan, Noel Y., Klessner, Jodi L., Beal, Flint M., Peters, Owen M., Metterville, Jake, Brown, Robert H., Jr, Ling, Karen K.Y., Rigo, Frank, Ozdinler, P. Hande, and Kiaei, Mahmoud
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- 2017
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7. Association of Gnrhr mRNA With the Stem Cell Determinant Musashi: A Mechanism for Leptin-Mediated Modulation of GnRHR Expression
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Odle, Angela K, Beneš, Helen, Melgar Castillo, Andrea, Akhter, Noor, Syed, Mohsin, Haney, Anessa, Allensworth-James, Melody, Hardy, Linda, Winter, Benjamin, Manoharan, Ragul, Syed, Raiyan, MacNicol, Melanie C, MacNicol, Angus M, and Childs, Gwen V
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- 2018
8. Women in Science: The Response
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Benditt, John, Richmond, Geraldine, Selgrade, MaryJane K., MacNicol, Melanie, Falk, Dean, Hancock, Kenneth G., Olson, Julie A., Jetter, Michele, Weaver, Ellen C., Bird, Stephanie J., Mims, Forrest M., Sung, Renee, Reisler, Hanna, Galloway, Denise, Linial, Maxine, Zakian, Virginia, Vigilant, Linda, Rolison, Debra R., Valentine, Joan Selverstone, Butler, Lynne M., and Hirsch, Charity
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- 1992
9. A novel mRNA 3' untranslated region translational control sequence regulates Xenopus Wee1 mRNA translation
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Wang, Yi Ying, Charlesworth, Amanda, Byrd, Shannon M., Gregerson, Robert, MacNicol, Melanie C., and MacNicol, Angus M.
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Messenger RNA ,Amphibians ,Biological sciences - Abstract
To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2008.02.033 Byline: Yi Ying Wang (a), Amanda Charlesworth (b)(c), Shannon M. Byrd (e), Robert Gregerson (f), Melanie C. MacNicol (b)(c), Angus M. MacNicol (a)(b)(d) Abstract: Cell cycle progression during oocyte maturation requires the strict temporal regulation of maternal mRNA translation. The intrinsic basis of this temporal control has not been fully elucidated but appears to involve distinct mRNA 3' UTR regulatory elements. In this study, we identify a novel translational control sequence (TCS) that exerts repression of target mRNAs in immature oocytes of the frog, Xenopus laevis, and can direct early cytoplasmic polyadenylation and translational activation during oocyte maturation. The TCS is functionally distinct from the previously characterized Musashi/polyadenylation response element (PRE) and the cytoplasmic polyadenylation element (CPE). We report that TCS elements exert translational repression in both the Wee1 mRNA 3' UTR and the pericentriolar material-1 (Pcm-1) mRNA 3' UTR in immature oocytes. During oocyte maturation, TCS function directs the early translational activation of the Pcm-1 mRNA. By contrast, we demonstrate that CPE sequences flanking the TCS elements in the Wee1 3' UTR suppress the ability of the TCS to direct early translational activation. Our results indicate that a functional hierarchy exists between these distinct 3' UTR regulatory elements to control the timing of maternal mRNA translational activation during oocyte maturation. Author Affiliation: (a) Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Slot 814, 4301 W. Markham St., Little Rock, AR 72205, USA (b) Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Slot 814, 4301 W. Markham St., Little Rock, AR 72205, USA (c) The Center for Translational Neuroscience, University of Arkansas for Medical Sciences, Slot 814, 4301 W. Markham St., Little Rock, AR 72205, USA (d) The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Slot 814, 4301 W. Markham St., Little Rock, AR 72205, USA (e) Committee on Developmental Biology, The University of Chicago, Chicago, IL, USA (f) Science Division, Lyon College, Batesville, AR, USA Article History: Received 5 June 2007; Revised 14 February 2008; Accepted 15 February 2008
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- 2008
10. Alterations in the TGFβ signaling pathway in myogenic progenitors with age
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Beggs, Marjorie L., Nagarajan, Radhakrishnan, Taylor-Jones, Jane M., Nolen, Greg, MacNicol, Melanie, and Peterson, Charlotte A.
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- 2004
11. Control of the Anterior Pituitary Cell Lineage Regulator POU1F1 by the Stem Cell Determinant Musashi.
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Allensworth-James, Melody, Banik, Jewel, Odle, Angela, Hardy, Linda, Lagasse, Alex, Moreira, Ana Rita Silva, Bird, Jordan, Thomas, Christian L, Avaritt, Nathan, Kharas, Michael G, Lengner, Christopher J, Byrum, Stephanie D, MacNicol, Melanie C, Childs, Gwen V, and MacNicol, Angus M
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STEM cells ,LEPTIN receptors ,SOMATOTROPIN ,NUCLEOTIDE sequence ,TRANSCRIPTION factors - 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. Among 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 posttranscriptional control of Pou1f1 messenger RNA (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 coassociated 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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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12. The Importance of Leptin to Reproduction.
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Childs, Gwen V, Odle, Angela K, MacNicol, Melanie C, and MacNicol, Angus M
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LEPTIN ,GONADOTROPIN ,MESSENGER RNA ,GONADOTROPIN releasing hormone ,KISSPEPTIN neurons ,LUTEINIZING hormone releasing hormone receptors ,GROWTH factors - Abstract
A healthy nutritional state is required for all aspects of reproduction and is signaled by the adipokine leptin. Leptin acts in a relatively narrow concentration range: too much or too little will compromise fertility. The leptin signal timing is important to prepubertal development in both sexes. In the brain, leptin acts on ventral premammillary neurons which signal kisspeptin (Kiss1) neurons to stimulate gonadotropin releasing hormone (GnRH) neurons. Suppression of Kiss1 neurons occurs when agouti-related peptide neurons are activated by reduced leptin, because leptin normally suppresses these orexigenic neurons. In the pituitary, leptin stimulates production of GnRH receptors (GnRHRs) and follicle-stimulating hormone at midcycle, by activating pathways that derepress actions of the messenger ribonucleic acid translational regulatory protein Musashi. In females, rising estrogen stimulates a rise in serum leptin, which peaks at midcycle, synchronizing with nocturnal luteinizing hormone pulses. The normal range of serum leptin levels (10-20 ng/mL) along with gonadotropins and growth factors promote ovarian granulosa and theca cell functions and oocyte maturation. In males, the prepubertal rise in leptin promotes testicular development. However, a decline in leptin levels in prepubertal boys reflects inhibition of leptin secretion by rising androgens. In adult males, leptin levels are 10% to 50% of those in females, and high leptin inhibits testicular function. The obesity epidemic has elucidated leptin resistance pathways, with too much leptin in either sex leading to infertility. Under conditions of balanced nutrition, however, the secretion of leptin is timed and regulated within a narrow level range that optimizes its trophic effects. [ABSTRACT FROM AUTHOR]
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- 2021
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13. Sex differences in somatotrope response to fasting: biphasic responses in male mice.
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Miles, Tiffany K., Moreira, Ana Rita Silva, Allensworth-James, Melody L., Odle, Angela K., Haney, Anessa C., MacNicol, Angus M., MacNicol, Melanie C., and Childs, Gwen V.
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SOMATOTROPIN ,GHRELIN receptors ,HORMONE receptors ,MESSENGER RNA ,SECRETION - Abstract
Anterior pituitary somatotropes are important metabolic sensors responding to leptin by secreting growth hormone (GH). However, reduced leptin signals caused by fasting have not always correlated with reduced serum GH. Reports show that fasting may stimulate or reduce GH secretion, depending on the species. Mechanisms underlying these distinct somatotrope responses to fasting remain unknown. To define the s omatotrope response to decreased leptin signaling we examined markers of somatotrope function over different time periods of fasting. Male mice were fasted for 24 and 48 h, with female mice fasted for 24 h compared to fed controls ad libitum. Body weight and serum glucose were reduced in both males and females, but, unexpectedly, serum leptin was reduced only in males. Furthermore, in males, serum GH levels showed a biphasic response with significant reductions at 24 h followed by a significant rise at 48 h, which coincided with the rise in serum ghrelin levels. In contrast, females showed an increase in serum GH at 24 h. We then explored mechanisms underlying the differential so matotrope responses seen in males and observed that pituitary levels of Gh mRNA increased, with no distinction between acute and prolonged fasting. By contrast, the Ghrhr mRNA (encoding GH releasing hormone receptor) and the Ghsr mRNA (encoding the ghrelin receptor) were both greatly increased at prolonged fasting times coincident with increased serum GH. These findings show sex differences in the somatotrope and ad ipocyte responses to fasting and support an adaptive role for somatotropes in males in response to multiple metabolic signals. [ABSTRACT FROM AUTHOR]
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- 2020
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14. Metabolic signalling to somatotrophs: Transcriptional and post‐transcriptional mediators.
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Allensworth‐James, Melody L., Odle, Angela K., Lim, Juchan, LaGasse, Alex N., Miles, Tiffany K., Hardy, Linda L., Haney, Anessa C., MacNicol, Melanie C., MacNicol, Angus M., and Childs, Gwen V.
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LEPTIN ,GROWTH hormone releasing factor ,SOMATOTROPIN receptors ,SOMATOTROPIN ,LEPTIN receptors ,BODY composition - Abstract
In normal individuals, pituitary somatotrophs optimise body composition by responding to metabolic signals from leptin. To identify mechanisms behind the regulation of somatotrophs by leptin, we used Cre‐LoxP technology to delete leptin receptors (LEPR) selectively in somatotrophs and developed populations purified by fluorescence‐activated cell sorting (FACS) that contained 99% somatotrophs. FACS‐purified, Lepr‐null somatotrophs showed reduced levels of growth hormone (GH), growth hormone‐releasing hormone receptor (GHRHR), and Pou1f1 proteins and Gh (females) and Ghrhr (both sexes) mRNAs. Pure somatotrophs also expressed thyroid‐stimulating hormone (TSH) and prolactin (PRL), both of which were reduced in pure somatotrophs lacking LEPR. This introduced five gene products that were targets of leptin. In the present study, we tested the hypothesis that leptin is both a transcriptional and a post‐transcriptional regulator of these gene products. Our tests showed that Pou1f1 and/or the Janus kinase/signal transducer and activator of transcription 3 transcriptional regulatory pathways are implicated in the leptin regulation of Gh or Ghrhr mRNAs. We then focused on potential actions by candidate microRNAs (miRNAs) with consensus binding sites on the 3' UTR of Gh or Ghrhr mRNAs. Somatotroph Lepr‐null deletion mutants expressed elevated levels of miRNAs including miR1197‐3p (in females), miR103‐3p and miR590‐3p (both sexes), which bind Gh mRNA, or miRNA‐325‐3p (elevated in both sexes), which binds Ghrhr mRNA. This elevation indicates repression of translation in the absence of LEPR. In addition, after detecting binding sites for Musashi on Tshb and Prl 3' UTR, we determined that Musashi1 repressed translation of both mRNAs in in vitro fluc assays and that Prl mRNA was enriched in Musashi immunoprecipitation assays. Finally, we tested ghrelin actions to determine whether its nitric oxide‐mediated signalling pathways would restore somatotroph functions in deletion mutants. Ghrelin did not restore either GHRH binding or GH secretion in vitro. These studies show an unexpectedly broad role for leptin with respect to maintaining somatotroph functions, including the regulation of PRL and TSH in subsets of somatotrophs that may be progenitor cells. [ABSTRACT FROM AUTHOR]
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- 2020
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15. Molecular Mechanisms of Pituitary Cell Plasticity.
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Childs, Gwen V., MacNicol, Angus M., and MacNicol, Melanie C.
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PHYSIOLOGY ,CELL populations ,CELLS - Abstract
The mechanisms that mediate plasticity in pituitary function have long been a subject of vigorous investigation. Early studies overcame technical barriers and challenged conceptual barriers to identify multipotential and multihormonal cell populations that contribute to diverse pituitary stress responses. Decades of intensive study have challenged the standard model of dedicated, cell type-specific hormone production and have revealed the malleable cellular fates that mediate pituitary responses. Ongoing studies at all levels, from animal physiology to molecular analyses, are identifying the mechanisms underlying this cellular plasticity. This review describes the findings from these studies that utilized state-of-the-art tools and techniques to identify mechanisms of plasticity throughout the pituitary and focuses on the insights brought to our understanding of pituitary function. [ABSTRACT FROM AUTHOR]
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- 2020
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16. Musashi interaction with poly(A)-binding protein is required for activation of target mRNA translation.
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Cragle, Chad E., MacNicol, Melanie C., Byrum, Stephanie D., Hardy, Linda L., Mackintosh, Samuel G., Richardson, William A., Gray, Nicola K., Childs, Gwen V., Tackett, Alan J., and MacNicol, Angus M.
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MESSENGER RNA , *SOMATIC cells , *PROTEINS , *STEM cells , *CELL differentiation , *OVUM - Abstract
The Musashi family of mRNA translational regulators controls both physiological and pathological stem cell self-renewal primarily by repressing target mRNAs that promote differentiation. In response to differentiation cues, Musashi can switch from a repressor to an activator of target mRNA translation. However, the molecular events that distinguish Musashi-mediated translational activation from repression are not understood. We have previously reported that Musashi function is required for the maturation of Xenopus oocytes and specifically for translational activation of specific dormant maternal mRNAs. Here, we employed MS to identify cellular factors necessary for Musashi-dependent mRNA translational activation. We report that Musashi1 needs to associate with the embryonic poly(A)-binding protein (ePABP) or the canonical somatic cell poly(A)-binding protein PABPC1 for activation of Musashi target mRNA translation. Co-immunoprecipitation studies demonstrated an increased Musashi1 interaction with ePABP during oocyte maturation. Attenuation of endogenous ePABP activity severely compromised Musashi function, preventing downstream signaling and blocking oocyte maturation. Ectopic expression of either ePABP or PABPC1 restored Musashi-dependent mRNA translational activation and maturation of ePABP-attenuated oocytes. Consistent with these Xenopus findings, PABPC1 remained associated with Musashi under conditions of Musashi target mRNA de-repression and translation during mammalian stem cell differentiation. Because association of Musashi1 with poly(A)-binding proteins has previously been implicated only in repression of Musashi target mRNAs, our findings reveal novel context-dependent roles for the interaction of Musashi with poly(A)-binding protein family members in response to extracellular cues that control cell fate. [ABSTRACT FROM AUTHOR]
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- 2019
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17. Sex-specific changes in postnatal GH and PRL secretion in somatotrope LEPR-null mice.
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Allensworth-James, Melody L., Odle, Angela, A, Anessa, MacNicol, Melanie, MacNicol, Angus, and Childs, Gwen
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PUERPERIUM ,LEPTIN receptors ,TRANSCRIPTION factors ,LABORATORY mice - Abstract
The developing pituitary is a rapidly changing environment that is constantly meeting the physiological demands of the growing organism. During early postnatal development, the anterior pituitary is refining patterns of anterior hormone secretion in response to numerous genetic factors. Our laboratory previously developed a somatotrope leptin receptor (LEPR) deletion mouse model that had decreased lean body mass, disrupted metabolism, decreased GH stores and was GH deficient as an adult. To understand how deletion of LEPR in somatotropes altered GH, we turned our attention to postnatal development. The current study examines GH, PRL, TSH, ACTH, LH and FSH secretion during postnatal days 4, 5, 8, 10 and 15 and compares age and sex differences. The LEPR mutants have dysregulation of GH (P < 0.03) and a reduced developmental prolactin peak in males (P < 0.04) and females (P < 0.002). There were no differences in weight between groups, and the postnatal leptin surge appeared to be normal. Percentages of immunolabeled GH cells were reduced in mutants compared with controls in all age groups by 35-61% in males and 41-44% in females. In addition, we measured pituitary expression of pituitary transcription factors, POU1F1 and PROP1. POU1F1 was reduced in mutant females at PND 10 (P < 0.009) and PND 15 (P < 0.02) but increased in males at PND 10 (P < 0.01). PROP1 was unchanged in female mutants but showed developmental increases at PND 5 (P < 0.02) and PND 15 (P < 0.01). These studies show that the dysfunction caused by LEPR deletion in somatotropes begins as early as neonatal development and involves developing GH and prolactin cells (somatolactotropes). [ABSTRACT FROM AUTHOR]
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- 2018
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18. Leptin regulation of Gonadotrope Gonadotropin-releasing Hormone receptors as a Metabolic Checkpoint and Gateway to reproductive Competence.
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Odle, Angela K., Akhter, Noor, Syed, Mohsin M., Allensworth-James, Melody L., Beneš, Helen, Melgar Castillo, Andrea I., MacNicol, Melanie C., MacNicol, Angus M., and Childs, Gwen V.
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LEPTIN ,GONADOTROPIN ,HORMONE receptors ,BIOTRANSFORMATION (Metabolism) ,HYPOTHALAMUS - Abstract
The adipokine leptin signals the body's nutritional status to the brain, and particularly, the hypothalamus. However, leptin receptors (LEPRs) can be found all throughout the body and brain, including the pituitary. It is known that leptin is permissive for reproduction, and mice that cannot produce leptin (Lep/Lep) are infertile. Many studies have pinpointed leptin's regulation of reproduction to the hypothalamus. However, LEPRs exist at all levels of the hypothalamic-pituitary-gonadal axis. We have previously shown that deleting the signaling portion of the LEPR specifically in gonadotropes impairs fertility in female mice. Our recent studies have targeted this regulation to the control of gonadotropin releasing hormone receptor (GnRHR) expression. The hypotheses presented here are twofold: (1) cyclic regulation of pituitary GnRHR levels sets up a target metabolic checkpoint for control of the reproductive axis and (2) multiple checkpoints are required for the metabolic signaling that regulates the reproductive axis. Here, we emphasize and explore the relationship between the hypothalamus and the pituitary with regard to the regulation of GnRHR. The original data we present strengthen these hypotheses and build on our previous studies. We show that we can cause infertility in 70% of female mice by deleting all isoforms of LEPR specifically in gonadotropes. Our findings implicate activin subunit (InhBa) mRNA as a potential leptin target in gonadotropes. We further show gonadotrope-specific upregulation of GnRHR protein (but not mRNA levels) following leptin stimulation. In order to try and understand this post-transcriptional regulation, we tested candidate miRNAs (identified with in silico analysis) that may be binding the Gnrhr mRNA. We show significant upregulation of one of these miRNAs in our gonadotrope-Lepr-null females. The evidence provided here, combined with our previous work, lay the foundation for metabolically regulated post-transcriptional control of the gonadotrope. We discuss possible mechanisms, including miRNA regulation and the involvement of the RNA binding protein, Musashi. We also demonstrate how this regulation may be vital for the dynamic remodeling of gonadotropes in the cycling female. Finally, we propose that the leptin receptivity of both the hypothalamus and the pituitary are vital for the body's ability to delay or slow reproduction during periods of low nutrition. [ABSTRACT FROM AUTHOR]
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- 2018
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19. Pedunculopontine Gamma Band Activity and Development.
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Garcia-Rill, Edgar, Luster, Brennon, Mahaffey, Susan, MacNicol, Melanie, Hyde, James R., D'Onofrio, Stasia M., and Phillips, Cristy
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RAPID eye movement sleep ,HEALTH - Abstract
This review highlights the most important discovery in the reticular activating system in the last 10 years, the manifestation of gamma band activity in cells of the reticular activating system (RAS), especially in the pedunculopontine nucleus, which is in charge of waking and rapid eye movement (REM) sleep. The identification of different cell groups manifesting P/Q-type Ca
2+ channels that control waking vs. those that manifest N-type channels that control REM sleep provides novel avenues for the differential control of waking vs. REM sleep. Recent discoveries on the development of this system can help explain the developmental decrease in REM sleep and the basic rest-activity cycle. [ABSTRACT FROM AUTHOR]- Published
- 2015
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20. Functional Integration of mRNA Translational Control Programs.
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MacNicol, Melanie C., Cragle, Chad E., Arumugam, Karthik, Fosso, Bruno, Pesole, Graziano, and MacNicol, Angus M.
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MESSENGER RNA , *GENETIC translation , *CELL cycle - Abstract
Regulated mRNA translation plays a key role in control of cell cycle progression in a variety of physiological and pathological processes, including in the self-renewal and survival of stem cells and cancer stem cells. While targeting mRNA translation presents an attractive strategy for control of aberrant cell cycle progression, mRNA translation is an underdeveloped therapeutic target. Regulated mRNAs are typically controlled through interaction with multiple RNA binding proteins (RBPs) but the mechanisms by which the functions of distinct RBPs bound to a common target mRNA are coordinated are poorly understood. The challenge now is to gain insight into these mechanisms of coordination and to identify the molecular mediators that integrate multiple, often conflicting, inputs. A first step includes the identification of altered mRNA ribonucleoprotein complex components that assemble on mRNAs bound by multiple, distinct RBPs compared to those recruited by individual RBPs. This review builds upon our knowledge of combinatorial control of mRNA translation during the maturation of oocytes from Xenopus laevis, to address molecular strategies that may mediate RBP diplomacy and conflict resolution for coordinated control of mRNA translational output. Continued study of regulated ribonucleoprotein complex dynamics promises valuable new insights into mRNA translational control and may suggest novel therapeutic strategies for the treatment of disease. [ABSTRACT FROM AUTHOR]
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- 2015
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21. Neural stem and progenitor cell fate transition requires regulation of Musashi1 function.
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MacNicol, Angus M., Hardy, Linda L., Spencer, Horace J., and MacNicol, Melanie C.
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PROGENITOR cells ,MESSENGER RNA ,CELLS ,RNA ,CELL cycle - Abstract
Background: There is increasing evidence of a pivotal role for regulated mRNA translation in control of developmental cell fate transitions. Physiological and pathological stem and progenitor cell self-renewal is maintained by the mRNA-binding protein, Musashi1 through repression of translation of key mRNAs encoding cell cycle inhibitory proteins. The mechanism by which Musashi1 function is modified to allow translation of these target mRNAs under conditions that require inhibition of cell cycle progression, is unknown. Results: In this study, we demonstrate that differentiation of primary embryonic rat neural stem/progenitor cells (NSPCs) or human neuroblastoma SH-SY5Y cells results in the rapid phosphorylation of Musashi1 on the evolutionarily conserved site serine 337 (S337). Phosphorylation of this site has been shown to be required for cell cycle control during the maturation of Xenopus oocytes. S337 phosphorylation in mammalian NSPCs and human SH-SY5Y cells correlates with the de-repression and translation of a Musashi reporter mRNA and with accumulation of protein from the endogenous Musashi target mRNA, p21
WAF1/CIP1 . Inhibition of Musashi regulatory phosphorylation, through expression of a phospho-inhibitory mutant Musashi1 S337A or over-expression of the wild-type Musashi, blocked differentiation of both NSPCs and SH-SY5Y cells. Musashi1 was similarly phosphorylated in NSPCs and SH-SY5Y cells under conditions of nutrient deprivation-induced cell cycle arrest. Expression of the Musashi1 S337A mutant protein attenuated nutrient deprivation-induced NSPC and SH-SY5Y cell death. Conclusions: Our data suggest that in response to environmental cues that oppose cell cycle progression, regulation of Musashi function is required to promote target mRNA translation and cell fate transition. Forced modulation of Musashi1 function may present a novel therapeutic strategy to oppose pathological stem cell self-renewal. [ABSTRACT FROM AUTHOR]- Published
- 2015
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- View/download PDF
22. The use of three-dimensional printing to produce in vitro slice chambers.
- Author
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Hyde, James, MacNicol, Melanie, Odle, Angela, and Garcia-Rill, Edgar
- Subjects
- *
PATCH-clamp techniques (Electrophysiology) , *THREE-dimensional printing , *3-D printers , *TISSUE slices , *STEREOLITHOGRAPHY , *EXCITABLE membranes , *BRAIN stem - Abstract
Background In recent years, 3D printing technology has become inexpensive and simple enough that any lab can own and use one of these printers. New method We explored the potential use of 3D printers for quickly and easily producing in vitro slice chambers for patch clamp electrophysiology. Slice chambers were produced using five available plastics: ABS, PLA, Nylon 618, Nylon 680, and T-glase. These “lab-made” chambers were also made using stereolithography through a professional printing service (Shapeways). This study measured intrinsic membrane properties of neurons in the brain stem pedunculopontine nucleus (PPN) and layer V pyramidal neurons in retrosplenial cortex. Results Nylon 680 and T-glase significantly hyperpolarized PPN neurons. ABS increased input resistance, decreased action potential amplitude, and increased firing frequency in pyramidal cortical neurons. To test long term exposure to each plastic, human neuroblastoma SHSY5Y cell cultures were exposed to each plastic for 1 week. ABS decreased cell counts while Nylon 618 and Shapeways plastics eliminated cells. Primary mouse pituitary cultures were also tested for 24-h exposure. ABS decreased cell counts while Nylon 618 and Shapeways plastics dramatically decreased cell counts. Comparison to existing methods Chambers can be quickly and inexpensively printed in the lab. ABS, PLA, Nylon 680, and T-glase plastics would suffice for many experiments instead of commercially produced slice chambers. Conclusions While these technologies are still in their infancy, they represent a powerful addition to the lab environment. With careful selection of print material, slice chambers can be quickly and inexpensively manufactured in the lab. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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23. Autoregulation of Musashi1 mRNA translation during Xenopus oocyte maturation.
- Author
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Arumugam, Karthik, MacNicol, Melanie C., and MacNicol, Angus M.
- Published
- 2012
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24. Ringo/Cyclin-dependent Kinase and Mitogen-activated Protein Kinase Signaling Pathways Regulate the Activity of the Cell Fate Determinant Musashi to Promote Cell Cycle Re-entry in Xenopus Oocytes.
- Author
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Arumugam, Karthik, MacNicol, Melanie C., Yiying Wang, Cragle, Chad E., Tackett, Alan J., Hardy, Linda L., and MacNicol, Angus M.
- Subjects
- *
CYCLIN-dependent kinases , *MITOGEN-activated protein kinases , *CELL cycle , *MESSENGER RNA , *GENETIC translation , *PHOSPHORYLATION - Abstract
Cell cycle re-entry during vertebrate oocyte maturation is mediated through translational activation of select target mRNAs, culminating in the activation of mitogen-activated protein kinase and cyclin B/cyclin-dependent kinase (CDK) signaling. The temporal order of targeted mRNA translation is crucial for cell cycle progression and is determined by the timing of activation of distinct mRNA-binding proteins. We have previously shown in oocytes from Xenopus laevis that the mRNA-binding protein Musashi targets translational activation of early class mRNAs including the mRNA encoding the Mos proto-oncogene. However, the molecular mechanism by which Musashi function is activated is unknown. We report here that activation of Musashi1 is mediated by Ringo/CDK signaling, revealing a novel role for early Ringo/CDK function. Interestingly, Musashi1 activation is subsequently sustained through mitogen-activated protein kinase signaling, the downstream effector of Mos mRNA translation, thus establishing a positive feedback loop to amplify Musashi function. The identified regulatory sites are present in mammalian Musashi proteins, and our data suggest that phosphorylation may represent an evolutionarily conserved mechanism to control Musashi-dependent target mRNA translation. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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- View/download PDF
25. Context-dependent regulation of Musashi-mediated mRNA translation and cell cycle regulation.
- Author
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MacNicol, Melanie C., Cragle, Chad E., and MacNicol, Angus M.
- Published
- 2011
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26. Enforcing temporal control of maternal mRNA translation during oocyte cell-cycle progression.
- Author
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Arumugam, Karthik, Yiying Wang, Hardy, Linda L., MacNicol, Melanie C., and MacNicol, Angus M.
- Subjects
MESSENGER RNA ,OLIGONUCLEOTIDES ,PROGESTERONE ,GENETIC translation ,CELL cycle - Abstract
Meiotic cell-cycle progression in progesterone-stimulated Xenopus oocytes requires that the translation of pre-existing maternal mRNAs occur in a strict temporal order. Timing of translation is regulated through elements within the mRNA 3′ untranslated region (3′ UTR), which respond to cell cycle-dependant signalling. One element that has been previously implicated in the temporal control of mRNA translation is the cytoplasmic polyadenylation element (CPE). In this study, we show that the CPE does not direct early mRNA translation. Rather, early translation is directed through specific early factors, including the Musashi-binding element (MBE) and the MBE-binding protein, Musashi. Our findings indicate that although the cyclin B5 3′ UTR contains both CPEs and an MBE, the MBE is the critical regulator of early translation. The cyclin B2 3′ UTR contains CPEs, but lacks an MBE and is translationally activated late in maturation. Finally, utilizing antisense oligonucleotides to attenuate endogenous Musashi synthesis, we show that Musashi is critical for the initiation of early class mRNA translation and for the subsequent activation of CPE-dependant mRNA translation. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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27. A novel regulatory element determines the timing of Mos mRNA translation during Xenopus oocyte maturation.
- Author
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Charlesworth, Amanda, Ridge, John A., King, Leslie A., MacNicol, Melanie C., and MacNicol, Angus M.
- Subjects
OVUM ,GENETIC translation ,MESSENGER RNA ,MITOGEN-activated protein kinases ,XENOPUS ,CELLULAR signal transduction - Abstract
Progression through vertebrate oocyte maturation requires that pre‐existing, maternally derived mRNAs be translated in a strict temporal order. The mechanism that controls the timing of oocyte mRNA translation is unknown. In this study we show that the early translational induction of the mRNA encoding the Mos proto‐oncogene is mediated through a novel regulatory element within the 3′ untranslated region of the Mos mRNA. This novel element is responsive to the MAP kinase signaling pathway and is distinct from the late acting, cdc2‐responsive, cytoplasmic polyadenylation element. Our findings suggest that the timing of maternal mRNA translation is controlled through signal transduction pathways targeting distinct 3′ UTR mRNA elements. [ABSTRACT FROM AUTHOR]
- Published
- 2002
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- View/download PDF
28. Post-Transcriptional Regulation of Gnrhr : A Checkpoint for Metabolic Control of Female Reproduction.
- Author
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Odle, Angela K., MacNicol, Melanie C., Childs, Gwen V., MacNicol, Angus M., and Misrahi, Micheline
- Subjects
- *
LUTEINIZING hormone releasing hormone receptors , *METABOLIC regulation , *RNA-binding proteins , *ESTRUS , *LEPTIN , *REPRODUCTION , *HORMONE receptors - Abstract
The proper expression of gonadotropin-releasing hormone receptors (GnRHRs) by pituitary gonadotropes is critical for maintaining maximum reproductive capacity. GnRH receptor expression must be tightly regulated in order to maintain the normal pattern of expression through the estrous cycle in rodents, which is believed to be important for interpreting the finely tuned pulses of GnRH from the hypothalamus. Much work has shown that Gnrhr expression is heavily regulated at the level of transcription. However, researchers have also discovered that Gnrhr is regulated post-transcriptionally. This review will discuss how RNA-binding proteins and microRNAs may play critical roles in the regulation of GnRHR expression. We will also discuss how these post-transcriptional regulators may themselves be affected by metabolic cues, specifically with regards to the adipokine leptin. All together, we present evidence that Gnrhr is regulated post-transcriptionally, and that this concept must be further explored in order to fully understand the complex nature of this receptor. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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- View/download PDF
29. Early expression of p107 is associated with 3T3-L1 adipocyte differentiation
- Author
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Liu, Kenian, Guan, Yu, MacNicol, Melanie C., MacNicol, Angus M., and McGehee Jr, Robert E.
- Subjects
- *
FAT cells , *CELL cycle - Abstract
In response to hormonal stimulation quiescent 3T3-L1 preadipocyte cells reenter the cell cycle and undergo a mitotic expansion phase prior to terminal differentiation. The cell cycle regulatory proteins p130 and p107 undergo dramatic changes in protein levels within 24 h of differentiation. The role of these proteins in regulating adipocyte mitotic clonal expansion and/or differentiation are unclear. It has recently been demonstrated that adipocyte proliferation can be uncoupled from adipocyte differentiation through the use of the pharmacological MEK inhibitor PD98059 or the tyrosine phosphatase inhibitor, sodium vanadate. We examined the expression of p130 and p107 in stimulated 3T3-L1 cells in the presence of either PD98059, U0126 or sodium vanadate. While inhibition of MEK blocked proliferation, the cells underwent differentiation normally. In contrast, vanadate blocked differentiation without affecting proliferation. Inhibition of MEK did not affect the increase in p107 expression in stimulated cells indicating that induction of p107 is independent of MAP kinase signaling. Vanadate treatment caused a significant delay in p107 expression in the first 24 h following stimulation. Under these conditions, p130 expression was relatively unchanged. Our results indicate that a rapid increase in p107 expression correlates with a commitment to undergo adipocyte differentiation. The data further suggest that the rapid induction of p107 is not required for cellular proliferation during the mitotic clonal expansion phase. Taken together, these findings provide correlative data that implicate p107 in the terminal differentiation, but not proliferation, of quiescent preadipocytes following hormonal stimulation. [Copyright &y& Elsevier]
- Published
- 2002
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- View/download PDF
30. Leptin : A Metabolic Signal for the Differentiation of Pituitary Cells
- Author
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Childs, Gwen V., MacNicol, Angus M., Syed, Mohsin M., Akhter, Noor, Miles, Tiffany K., Allensworth-James, Melody L., MacNicol, Melanie C., and Odle, Angela K.
- Subjects
Medical - Abstract
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.
- Published
- 2020
31. Anterior Pituitary Transcriptomics Following a High-Fat Diet: Impact of Oxidative Stress on Cell Metabolism.
- Author
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Miles TK, Odle AK, Byrum SD, Lagasse A, Haney A, Ortega VG, Bolen CR, Banik J, Reddick MM, Herdman A, MacNicol MC, MacNicol AM, and Childs GV
- Subjects
- Male, Female, Mice, Animals, Weight Gain, Gene Expression Profiling, Oxidative Stress, Mice, Inbred C57BL, Diet, High-Fat adverse effects, Obesity metabolism
- Abstract
Anterior pituitary cell function requires a high level of protein synthesis and secretion which depend heavily on mitochondrial adenosine triphosphate production and functional endoplasmic reticula. Obesity adds stress to tissues, requiring them to adapt to inflammation and oxidative stress, and adding to their allostatic load. We hypothesized that pituitary function is vulnerable to the stress of obesity. Here, we utilized a 10- to 15-week high-fat diet (HFD, 60%) in a thermoneutral environment to promote obesity, testing both male and female FVB.129P mice. We quantified serum hormones and cytokines, characterized the metabolic phenotype, and defined changes in the pituitary transcriptome using single-cell RNA-sequencing analysis. Weight gain was significant by 3 weeks in HFD mice, and by 10 weeks all HFD groups had gained 20 g. HFD females (15 weeks) had increased energy expenditure and decreased activity. All HFD groups showed increases in serum leptin and decreases in adiponectin. HFD caused increased inflammatory markers: interleukin-6, resistin, monocyte chemoattractant protein-1, and tumor necrosis factorα. HFD males and females also had increased insulin and increased TSH, and HFD females had decreased serum prolactin and growth hormone pulse amplitude. Pituitary single-cell transcriptomics revealed modest or no changes in pituitary cell gene expression from HFD males after 10 or 15 weeks or from HFD females after 10 weeks. However, HFD females (15 weeks) showed significant numbers of differentially expressed genes in lactotropes and pituitary stem cells. Collectively, these studies reveal that pituitary cells from males appear to be more resilient to the oxidative stress of obesity than females and identify the most vulnerable pituitary cell populations in females., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
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32. Evasion of regulatory phosphorylation by an alternatively spliced isoform of Musashi2.
- Author
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MacNicol MC, Cragle CE, McDaniel FK, Hardy LL, Wang Y, Arumugam K, Rahmatallah Y, Glazko GV, Wilczynska A, Childs GV, Zhou D, and MacNicol AM
- Subjects
- Animals, Cell Line, Humans, Phosphorylation, Protein Isoforms metabolism, Gene Expression Regulation, Protein Processing, Post-Translational, RNA-Binding Proteins metabolism
- Abstract
The Musashi family of RNA binding proteins act to promote stem cell self-renewal and oppose cell differentiation predominantly through translational repression of mRNAs encoding pro-differentiation factors and inhibitors of cell cycle progression. During tissue development and repair however, Musashi repressor function must be dynamically regulated to allow cell cycle exit and differentiation. The mechanism by which Musashi repressor function is attenuated has not been fully established. Our prior work indicated that the Musashi1 isoform undergoes site-specific regulatory phosphorylation. Here, we demonstrate that the canonical Musashi2 isoform is subject to similar regulated site-specific phosphorylation, converting Musashi2 from a repressor to an activator of target mRNA translation. We have also characterized a novel alternatively spliced, truncated isoform of human Musashi2 (variant 2) that lacks the sites of regulatory phosphorylation and fails to promote translation of target mRNAs. Consistent with a role in opposing cell cycle exit and differentiation, upregulation of Musashi2 variant 2 was observed in a number of cancers and overexpression of the Musashi2 variant 2 isoform promoted cell transformation. These findings indicate that alternately spliced isoforms of the Musashi protein family possess distinct functional and regulatory properties and suggest that differential expression of Musashi isoforms may influence cell fate decisions.
- Published
- 2017
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- View/download PDF
33. A Sex-Dependent, Tropic Role for Leptin in the Somatotrope as a Regulator of POU1F1 and POU1F1-Dependent Hormones.
- Author
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Odle AK, Allensworth-James ML, Akhter N, Syed M, Haney AC, MacNicol M, MacNicol AM, and Childs GV
- Subjects
- Animals, Female, Genes, Reporter, Growth Hormone analysis, Growth Hormone metabolism, Integrases, Male, Mice, Prolactin metabolism, Thyrotropin metabolism, Flow Cytometry methods, Leptin metabolism, Sex Characteristics, Somatotrophs metabolism, Transcription Factor Pit-1 metabolism
- Abstract
Pituitary somatotropes perform the key function of coordinating organismic growth and body composition with metabolic signals. However, the mechanism by which they sense and respond to metabolic signals via the adipokine leptin is unknown. The complex interplay between the heterogeneous cell types of the pituitary confounds the identification of somatotrope-specific mechanisms. Somatotropes represent 30%-40% of the anterior pituitary population and are derived from a lineage of cells that are activated by the Pit-Oct-Unc domain family domain class 1 transcription factor 1 (POU1F1) to produce GH, prolactin (PRL). and TSH. To determine the mechanism by which leptin controls somatotrope function, we used Cre-LoxP technology and fluorescence-activated cell sorting to purify and study control or leptin receptor-deleted (Lepr null) somatotropes. We report that Lepr-null somatotropes show significant reductions in GH protein (GH) and Gh mRNA. By contrast, enzyme immunoassays detected no changes in ACTH, LH, and FSH levels in mutants, indicating that the control of these hormones is independent of leptin signaling to somatotropes. Reduced TSH and PRL levels were also observed, but interestingly, this reduction occurred only in in Lepr-null somatotropes from mutant females and not from males. Consistent with the sex-specific reduction in Gh mRNA, TSH, and PRL, enzyme immunoassays detected a sex-specific reduction in POU1F1 protein levels in adult female Lepr-null somatotropes. Collectively, this study of purified Lepr-null somatotropes has uncovered an unexpected tropic role for leptin in the control of POU1F1 and all POU1F1-dependent hormones. This supports a broader role for somatotropes as metabolic sensors including sex-specific responses to leptin.
- Published
- 2016
- Full Text
- View/download PDF
34. Developmental timing of mRNA translation--integration of distinct regulatory elements.
- Author
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MacNicol MC and MacNicol AM
- Subjects
- Animals, Humans, Models, Biological, Signal Transduction, Systems Integration, Time Factors, Growth and Development genetics, Protein Biosynthesis genetics, Protein Biosynthesis physiology, Regulatory Sequences, Nucleic Acid physiology
- Abstract
Targeted mRNA translation is emerging as a critical mechanism to control gene expression during developmental processes. Exciting new findings have revealed a critical role for regulatory elements within the mRNA untranslated regions to direct the timing of mRNA translation. Regulatory elements can be targeted by sequence-specific binding proteins to direct either repression or activation of mRNA translation in response to developmental signals. As new regulatory elements continue to be identified it has become clear that targeted mRNAs can contain multiple regulatory elements, directing apparently contradictory translational patterns. How is this complex regulatory input integrated? In this review, we focus on a new challenge area-how sequence-specific RNA binding proteins respond to developmental signals and functionally integrate to regulate the extent and timing of target mRNA translation. We discuss current understanding with a particular emphasis on the control of cell cycle progression that is mediated through a complex interplay of distinct mRNA regulatory elements during Xenopus oocyte maturation., ((c) 2010 Wiley-Liss, Inc.)
- Published
- 2010
- Full Text
- View/download PDF
35. Mos 3' UTR regulatory differences underlie species-specific temporal patterns of Mos mRNA cytoplasmic polyadenylation and translational recruitment during oocyte maturation.
- Author
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Prasad CK, Mahadevan M, MacNicol MC, and MacNicol AM
- Subjects
- Animals, Blotting, Western, DNA Primers genetics, Electrophoretic Mobility Shift Assay, Humans, Mutagenesis, Site-Directed, Oocytes metabolism, Proto-Oncogene Mas, RNA, Messenger genetics, Species Specificity, Transcription Factors metabolism, Xenopus, mRNA Cleavage and Polyadenylation Factors metabolism, 3' Untranslated Regions genetics, Gene Expression Regulation, Developmental genetics, Genes, mos genetics, Oocytes growth & development, Polyadenylation genetics, RNA, Messenger metabolism
- Abstract
The Mos proto-oncogene is a critical regulator of vertebrate oocyte maturation. The maturation-dependent translation of Mos protein correlates with the cytoplasmic polyadenylation of the maternal Mos mRNA. However, the precise temporal requirements for Mos protein function differ between oocytes of model mammalian species and oocytes of the frog Xenopus laevis. Despite the advances in model organisms, it is not known if the translation of the human Mos mRNA is also regulated by cytoplasmic polyadenylation or what regulatory elements may be involved. We report that the human Mos 3' untranslated region (3' UTR) contains a functional cytoplasmic polyadenylation element (CPE) and demonstrate that the endogenous Mos mRNA undergoes maturation-dependent cytoplasmic polyadenylation in human oocytes. The human Mos 3' UTR interacts with the human CPE-binding protein and exerts translational control on a reporter mRNA in the heterologous Xenopus oocyte system. Unlike the Xenopus Mos mRNA, which is translationally activated by an early acting Musashi/polyadenylation response element (PRE)-directed control mechanism, the translational activation of the human Mos 3' UTR is dependent on a late acting CPE-dependent process. Taken together, our findings suggest a fundamental difference in the 3' UTR regulatory mechanisms controlling the temporal induction of maternal Mos mRNA polyadenylation and translational activation during Xenopus and mammalian oocyte maturation.
- Published
- 2008
- Full Text
- View/download PDF
36. Function and regulation of the mammalian Musashi mRNA translational regulator.
- Author
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MacNicol AM, Wilczynska A, and MacNicol MC
- Subjects
- Animals, Cell Proliferation, Humans, Neoplasms metabolism, Neoplasms pathology, Neurons cytology, PC12 Cells, Protein Transport, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Stem Cells cytology, Subcellular Fractions metabolism, Nerve Tissue Proteins metabolism, Protein Biosynthesis
- Abstract
The evolutionarily conserved RNA-binding protein, Musashi, regulates neural stem cell self-renewal. Musashi expression is also indicative of stem cell populations in breast and intestinal tissues and is linked to cell overproliferation in cancers of these tissues. Musashi has been primarily implicated as a repressor of target mRNAs in stem cell populations. However, little is known about the mechanism by which Musashi exerts mRNA translational control or how Musashi function is regulated. Recent findings in oocytes of the frog, Xenopus, indicate an unexpected role for Musashi as an activator of a number of maternal mRNAs during meiotic cell cycle progression. Given the importance of Musashi function in stem cell biology and the implications of aberrant Musashi expression in cancer, it is critical that we understand the molecular processes that regulate Musashi function.
- Published
- 2008
- Full Text
- View/download PDF
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