title: Knockout of RNA Binding Protein MSI2 Impairs Follicle Development in the Mouse Ovary: Characterization of MSI1 and MSI2 during Folliculogenesis.
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.
authors.affiliation: School of Environmental and Life Sciences, University of Newcastle, Callaghan NSW 2308, Australia. jessie.sutherland@newcastle.edu.au.|School of Biomedical Sciences & Pharmacy, University of Newcastle, Callaghan NSW 2308, Australia. jessie.sutherland@newcastle.edu.au.
authors.forename: Jessie M
authors.initials: JM
authors.lastname: Sutherland
authors.affiliation: School of Environmental and Life Sciences, University of Newcastle, Callaghan NSW 2308, Australia. asobinoff@cmri.org.au.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Sobinoff
authors.affiliation: School of Environmental and Life Sciences, University of Newcastle, Callaghan NSW 2308, Australia. Kara.gunter@uon.edu.au.
authors.forename: Kara M
authors.initials: KM
authors.lastname: Gunter
authors.affiliation: School of Environmental and Life Sciences, University of Newcastle, Callaghan NSW 2308, Australia. barbara.fraser@newcastle.edu.au.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Fraser
authors.affiliation: School of Environmental and Life Sciences, University of Newcastle, Callaghan NSW 2308, Australia. victoria.pye@newcastle.edu.au.
authors.forename: Victoria
authors.initials: V
authors.lastname: Pye
authors.affiliation: School of Environmental and Life Sciences, University of Newcastle, Callaghan NSW 2308, Australia. ilana.bernstein@newcastle.edu.au.
authors.forename: Ilana R
authors.initials: IR
authors.lastname: Bernstein
authors.affiliation: School of Biomedical Sciences & Pharmacy, University of Newcastle, Callaghan NSW 2308, Australia. evan.boon@uon.edu.au.
authors.forename: Evan
authors.initials: E
authors.lastname: Boon
authors.affiliation: Anatomy and Neuroscience, University of Melbourne, Parkville VIC 3010, Australia. n.siddall@unimelb.edu.au.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Siddall
authors.affiliation: Differentiation and Cancer Program, Center for Genomic Regulation and UPF, Barcelona 08000, Spain. marisa.deandres@crg.eu.
authors.forename: Luisa I
authors.initials: LI
authors.lastname: De Andres
authors.affiliation: Anatomy and Neuroscience, University of Melbourne, Parkville VIC 3010, Australia. g.hime@unimelb.edu.au.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Hime
authors.affiliation: School of Biomedical Sciences & Pharmacy, University of Newcastle, Callaghan NSW 2308, Australia. janet.holt@newcastle.edu.au.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Holt
authors.affiliation: Differentiation and Cancer Program, Center for Genomic Regulation and UPF, Barcelona 08000, Spain. Thomas.Graf@crg.eu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Graf
authors.affiliation: School of Environmental and Life Sciences, University of Newcastle, Callaghan NSW 2308, Australia. Eileen.mclaughlin@newcastle.edu.au.
authors.forename: Eileen A
authors.initials: EA
authors.lastname: McLaughlin
mesh_terms: D000818:Animals; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D051379:Mice; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics*; D006080:Ovarian Follicle / Q000254:growth & development* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C104786:Msi1h protein, mouse; C499059:Msi2h protein, mouse; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins
keywords: Musashi; fertility; granulosa cell; oocyte; oogenesis