Progranulin is an FMRP target that influences macroorchidism but not behaviour in a mouse model of Fragile X Syndrome
A growing body of evidence has implicated progranulin in neurodevelopment and indicated that aberrant progranulin expression may be involved in neurodevelopmental disease. Specifically, increased progranulin expression in the prefrontal cortex has been suggested to be pathologically relevant in male...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Current Research in Neurobiology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2665945X23000220 |
| _version_ | 1827917394146754560 |
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| author | Benjamin Life Luis E.B. Bettio Ilse Gantois Brian R. Christie Blair R. Leavitt |
| author_facet | Benjamin Life Luis E.B. Bettio Ilse Gantois Brian R. Christie Blair R. Leavitt |
| author_sort | Benjamin Life |
| collection | DOAJ |
| description | A growing body of evidence has implicated progranulin in neurodevelopment and indicated that aberrant progranulin expression may be involved in neurodevelopmental disease. Specifically, increased progranulin expression in the prefrontal cortex has been suggested to be pathologically relevant in male Fmr1 knockout (Fmr1 KO) mice, a mouse model of Fragile X Syndrome (FXS). Further investigation into the role of progranulin in FXS is warranted to determine if therapies that reduce progranulin expression represent a viable strategy for treating patients with FXS. Several key knowledge gaps remain. The mechanism of increased progranulin expression in Fmr1 KO mice is poorly understood and the extent of progranulin's involvement in FXS-like phenotypes in Fmr1 KO mice has been incompletely explored. To this end, we have performed a thorough characterization of progranulin expression in Fmr1 KO mice. We find that the phenomenon of increased progranulin expression is post-translational and tissue-specific. We also demonstrate for the first time an association between progranulin mRNA and FMRP, suggesting that progranulin mRNA is an FMRP target. Subsequently, we show that progranulin over-expression in Fmr1 wild-type mice causes reduced repetitive behaviour engagement in females and mild hyperactivity in males but is largely insufficient to recapitulate FXS-associated behavioural, morphological, and electrophysiological abnormalities. Lastly, we determine that genetic reduction of progranulin expression on an Fmr1 KO background reduces macroorchidism but does not alter other FXS-associated behaviours or biochemical phenotypes. |
| first_indexed | 2024-03-13T03:28:11Z |
| format | Article |
| id | doaj.art-3f8d6fe70d1643a18042d4f2ae19847b |
| institution | Directory Open Access Journal |
| issn | 2665-945X |
| language | English |
| last_indexed | 2024-03-13T03:28:11Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Current Research in Neurobiology |
| spelling | doaj.art-3f8d6fe70d1643a18042d4f2ae19847b2023-06-25T04:43:35ZengElsevierCurrent Research in Neurobiology2665-945X2023-01-015100094Progranulin is an FMRP target that influences macroorchidism but not behaviour in a mouse model of Fragile X SyndromeBenjamin Life0Luis E.B. Bettio1Ilse Gantois2Brian R. Christie3Blair R. Leavitt4Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6H 0B3, Canada; BC Children's Hospital Research Institute, Vancouver, BC, V5Z 4H4, CanadaDivision of Medical Sciences, University of Victoria, Victoria, BC, V8P 5C2, CanadaDepartment of Biochemistry, McGill University, Montreal, H3A 2T5, Quebec, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, H3A 2T5, Quebec, CanadaDivision of Medical Sciences, University of Victoria, Victoria, BC, V8P 5C2, Canada; Island Medical Program, University of British Columbia, Victoria, BC, V8P 5C2, Canada; Center for Brain Health, University of British Columbia, Vancouver, BC, V6T 1Z3, CanadaCentre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6H 0B3, Canada; BC Children's Hospital Research Institute, Vancouver, BC, V5Z 4H4, Canada; Division of Neurology, Department of Medicine, University of British Columbia Hospital, Vancouver, BC, V6T 2B5, Canada; Center for Brain Health, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada; Corresponding author. Centre for Molecular Medicine & Therapeutics, Department of Medical Genetics, University of British Columbia, B.C. Children’s Hospital, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.A growing body of evidence has implicated progranulin in neurodevelopment and indicated that aberrant progranulin expression may be involved in neurodevelopmental disease. Specifically, increased progranulin expression in the prefrontal cortex has been suggested to be pathologically relevant in male Fmr1 knockout (Fmr1 KO) mice, a mouse model of Fragile X Syndrome (FXS). Further investigation into the role of progranulin in FXS is warranted to determine if therapies that reduce progranulin expression represent a viable strategy for treating patients with FXS. Several key knowledge gaps remain. The mechanism of increased progranulin expression in Fmr1 KO mice is poorly understood and the extent of progranulin's involvement in FXS-like phenotypes in Fmr1 KO mice has been incompletely explored. To this end, we have performed a thorough characterization of progranulin expression in Fmr1 KO mice. We find that the phenomenon of increased progranulin expression is post-translational and tissue-specific. We also demonstrate for the first time an association between progranulin mRNA and FMRP, suggesting that progranulin mRNA is an FMRP target. Subsequently, we show that progranulin over-expression in Fmr1 wild-type mice causes reduced repetitive behaviour engagement in females and mild hyperactivity in males but is largely insufficient to recapitulate FXS-associated behavioural, morphological, and electrophysiological abnormalities. Lastly, we determine that genetic reduction of progranulin expression on an Fmr1 KO background reduces macroorchidism but does not alter other FXS-associated behaviours or biochemical phenotypes.http://www.sciencedirect.com/science/article/pii/S2665945X23000220ProgranulinFragile X SyndromeAutism spectrum disorderNeurodevelopmentMouse models |
| spellingShingle | Benjamin Life Luis E.B. Bettio Ilse Gantois Brian R. Christie Blair R. Leavitt Progranulin is an FMRP target that influences macroorchidism but not behaviour in a mouse model of Fragile X Syndrome Current Research in Neurobiology Progranulin Fragile X Syndrome Autism spectrum disorder Neurodevelopment Mouse models |
| title | Progranulin is an FMRP target that influences macroorchidism but not behaviour in a mouse model of Fragile X Syndrome |
| title_full | Progranulin is an FMRP target that influences macroorchidism but not behaviour in a mouse model of Fragile X Syndrome |
| title_fullStr | Progranulin is an FMRP target that influences macroorchidism but not behaviour in a mouse model of Fragile X Syndrome |
| title_full_unstemmed | Progranulin is an FMRP target that influences macroorchidism but not behaviour in a mouse model of Fragile X Syndrome |
| title_short | Progranulin is an FMRP target that influences macroorchidism but not behaviour in a mouse model of Fragile X Syndrome |
| title_sort | progranulin is an fmrp target that influences macroorchidism but not behaviour in a mouse model of fragile x syndrome |
| topic | Progranulin Fragile X Syndrome Autism spectrum disorder Neurodevelopment Mouse models |
| url | http://www.sciencedirect.com/science/article/pii/S2665945X23000220 |
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