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Biomolecules 2015, 5(3), 1228-1244; https://doi.org/10.3390/biom5031228

Knockout of RNA Binding Protein MSI2 Impairs Follicle Development in the Mouse Ovary: Characterization of MSI1 and MSI2 during Folliculogenesis

1
School of Environmental and Life Sciences, University of Newcastle, Callaghan NSW 2308, Australia
2
School of Biomedical Sciences & Pharmacy, University of Newcastle, Callaghan NSW 2308, Australia
3
Anatomy and Neuroscience, University of Melbourne, Parkville VIC 3010, Australia
4
Differentiation and Cancer Program, Center for Genomic Regulation and UPF, Barcelona 08000, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: André P. Gerber
Received: 11 March 2015 / Revised: 29 May 2015 / Accepted: 9 June 2015 / Published: 26 June 2015
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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Abstract

Characterizing the mechanisms underlying follicle development in the ovary is crucial to understanding female fertility and is an area of increasing research interest. The RNA binding protein Musashi is essential for post-transcriptional regulation of oocyte maturation in Xenopus and is expressed during ovarian development in Drosophila. In mammals Musashi is important for spermatogenesis and male fertility, but its role in the ovary has yet to be characterized. In this study we determined the expression of mammalian Musashi proteins MSI1 and MSI2 during mouse folliculogenesis, and through the use of a MSI2-specific knockout mouse model we identified that MSI2 is essential for normal follicle development. Time-course characterization of MSI1 and MSI2 revealed distinct differences in steady-state mRNA levels and protein expression/localization at important developmental time-points during folliculogenesis. Using a gene-trap mouse model that inactivates Msi2, we observed a significant decrease in ovarian mass, and change in follicle-stage composition due to developmental blocking of antral stage follicles and pre-antral follicle loss through atresia. We also confirmed that hormonally stimulated Msi2-deficient mice produce significantly fewer MII oocytes (60.9% less than controls, p < 0.05). Furthermore, the majority of these oocytes are of poor viability (62.2% non-viable/apoptotic, p < 0.05), which causes a reduction in female fertility evidenced by decreased litter size in Msi2-deficient animals (33.1% reduction to controls, p < 0.05). Our findings indicate that MSI1 and MSI2 display distinct expression profiles during mammalian folliculogenesis and that MSI2 is required for pre-antral follicle development. View Full-Text
Keywords: fertility; Musashi; oocyte; granulosa cell; oogenesis fertility; Musashi; oocyte; granulosa cell; oogenesis
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Sutherland, J.M.; Sobinoff, A.P.; Gunter, K.M.; Fraser, B.A.; Pye, V.; Bernstein, I.R.; Boon, E.; Siddall, N.A.; De Andres, L.I.; Hime, G.R.; Holt, J.E.; Graf, T.; McLaughlin, E.A. Knockout of RNA Binding Protein MSI2 Impairs Follicle Development in the Mouse Ovary: Characterization of MSI1 and MSI2 during Folliculogenesis. Biomolecules 2015, 5, 1228-1244.

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{"cc_re__cc_re__cc_by_3_0": ["eta name=\"dc.creator\" content=\"Gary R. Hime\">\n<meta name=\"dc.creator\" content=\"Janet E. Holt\">\n<meta name=\"dc.creator\" content=\"Thomas Graf\">\n<meta name=\"dc.creator\" content=\"Eileen A. McLaughlin\">\n<meta name=\"dc.type\" content=\"Article\">\n<meta name=\"dc.source\" content=\"Biomolecules 2015, Vol. 5, Pages 1228-1244\">\n<meta name=\"dc.date\" content=\"2015-06-26\">\n<meta name=\"dc.identifier\" content=\"10.3390/biom5031228\">\n<meta name=\"dc.publisher\" content=\"Multidisciplinary Digital Publishing Institute\">\n<meta name=\"dc.rights\" content=\"http://creativecommons.org/licenses/by/3.0/\">\n<meta name=\"dc.format\" content=\"application/pdf\">\n<meta name=\"dc.language\" content=\"en\">\n<meta name=\"dc.description\" content=\"Characterizing the mechanisms underlying follicle development in the ovary is crucial to understanding female fertility and is an area of increasing research interest. The RNA binding protein Musashi is essential for post-transcriptional regulation of oocyte maturation in Xenopus and is expressed during ovarian development in Drosophila. In mammals Musashi is important f"], "cc_re__cc_re__cc_by_4_0": [" 6 months. The average number of live births per litter was recorded. &lt;italic&gt;n&lt;/italic&gt; = 3 individual Wt \u00d7 Wt breeding pairs, &lt;italic&gt;n&lt;/italic&gt; = 10 individual Msi2&lt;sup&gt;Gt/Gt&lt;/sup&gt; (female) and Wt (male) pairs. * denotes &lt;italic&gt;p&lt;/italic&gt; &amp;lt; 0.05.&lt;/p&gt;\n                                                            \"></a></div>\n<div class=\"licenseText in-tab\" style=\"padding: 1em 0;\">\nThis is an open access article distributed under the <a href=\"https://creativecommons.org/licenses/by/4.0/\" target=\"_blank\">Creative Commons Attribution License</a> which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).\n</div>\n</div>\n<div id=\"tabs-4\" class=\"ui-tabs-panel\">\n<a id=\"suppl_id\" name=\"supplementary\"></a>\n<h1>Supplementary material</h1>\n<div class=\"in-tab\">\n<ul style=\"margin:0; list-style: none;\">\n<li><a name=\"supplementary_file1\"></a><b>Supplementary File 1:</b>\n<p>\n<a href=\"/2218-273X/5/3/1228/s1\">\nSupplementary\n</a>\n(PDF, 69"], "copyright__copyright__copyright": [" L.I.; Hime, G.R.; Holt, J.E.; Graf, T.; McLaughlin, E.A. Knockout of RNA Binding Protein MSI2 Impairs Follicle Development in the Mouse Ovary: Characterization of MSI1 and MSI2 during Folliculogenesis. Biomolecules 2015, 5, 1228-1244.\n\nShow more citation formats Show less citations formats\n\nRelated Articles\n\nArticle Metrics\n\nArticle Access Statistics\n\n1\n\nComments\n\n[Return to top]\nBiomolecules EISSN 2218-273X Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert\nBack to Top", " L.I.; Hime, G.R.; Holt, J.E.; Graf, T.; McLaughlin, E.A. Knockout of RNA Binding Protein MSI2 Impairs Follicle Development in the Mouse Ovary: Characterization of MSI1 and MSI2 during Folliculogenesis. Biomolecules 2015, 5, 1228-1244.\n\nShow more citation formats Show less citations formats\n\nRelated Articles\n\nArticle Metrics\n\nArticle Access Statistics\n\n1\n\nComments\n\n[Return to top]\nBiomolecules EISSN 2218-273X Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert\nBack to Top", " L.I.; Hime, G.R.; Holt, J.E.; Graf, T.; McLaughlin, E.A. Knockout of RNA Binding Protein MSI2 Impairs Follicle Development in the Mouse Ovary: Characterization of MSI1 and MSI2 during Folliculogenesis. Biomolecules 2015, 5, 1228-1244.\n\nShow more citation formats Show less citations formats\n\nRelated Articles\n\nArticle Metrics\n\nArticle Access Statistics\n\n1\n\nComments\n\n[Return to top]\nBiomolecules EISSN 2218-273X Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert\nBack to Top"]}