Reduced Granule Cell Proliferation and Molecular Dysregulation in the Cerebellum of Lysosomal Acid Phosphatase 2 (ACP2) Mutant Mice
Lysosomal acid phosphatase 2 (<i>Acp2</i>) mutant mice (naked-ataxia, <i>nax</i>) have a severe cerebellar cortex defect with a striking reduction in the number of granule cells. Using a combination of in vivo and in vitro immunohistochemistry, Western blotting, BrdU assays,...
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MDPI AG
2021-03-01
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| Series: | International Journal of Molecular Sciences |
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| author | Xiaodan Jiao Maryam Rahimi Balaei Ejlal Abu-El-Rub Filippo Casoni Hassan Pezeshgi Modarres Sanjiv Dhingra Jiming Kong Giacomo G. Consalez Hassan Marzban |
| author_facet | Xiaodan Jiao Maryam Rahimi Balaei Ejlal Abu-El-Rub Filippo Casoni Hassan Pezeshgi Modarres Sanjiv Dhingra Jiming Kong Giacomo G. Consalez Hassan Marzban |
| author_sort | Xiaodan Jiao |
| collection | DOAJ |
| description | Lysosomal acid phosphatase 2 (<i>Acp2</i>) mutant mice (naked-ataxia, <i>nax</i>) have a severe cerebellar cortex defect with a striking reduction in the number of granule cells. Using a combination of in vivo and in vitro immunohistochemistry, Western blotting, BrdU assays, and RT-qPCR, we show downregulation of MYCN and dysregulation of the SHH signaling pathway in the <i>nax</i> cerebellum. MYCN protein expression is significantly reduced at P10, but not at the peak of proliferation at around P6 when the number of granule cells is strikingly reduced in the <i>nax</i> cerebellum. Despite the significant role of the SHH–MycN pathway in granule cell proliferation, our study suggests that a broader molecular pathway and additional mechanisms regulating granule cell development during the clonal expansion period are impaired in the <i>nax</i> cerebellum. In particular, our results indicate that downregulation of the protein synthesis machinery may contribute to the reduced number of granule cells in the <i>nax</i> cerebellum. |
| first_indexed | 2024-03-10T13:12:18Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T13:12:18Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-21a6e473246048b5a41b5b85121826112023-11-21T10:36:59ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01226299410.3390/ijms22062994Reduced Granule Cell Proliferation and Molecular Dysregulation in the Cerebellum of Lysosomal Acid Phosphatase 2 (ACP2) Mutant MiceXiaodan Jiao0Maryam Rahimi Balaei1Ejlal Abu-El-Rub2Filippo Casoni3Hassan Pezeshgi Modarres4Sanjiv Dhingra5Jiming Kong6Giacomo G. Consalez7Hassan Marzban8Department of Human Anatomy and Cell Science, The Children’s Hospital Research Institute of Manitoba (CHRIM), Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0W2, CanadaDepartment of Human Anatomy and Cell Science, The Children’s Hospital Research Institute of Manitoba (CHRIM), Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0W2, CanadaDepartment of Physiology and Pathophysiology, Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0W2, CanadaDivision of Neuroscience, San Raffaele Scientific Institute, San Raffaele University, 20132 Milan, ItalyBioMEMS and Bioinspired Microfluidic Laboratory, Department of Mechanical and Manufacturing Engineering, University of Calgary, Calgary, AB T2N 1N4, CanadaDepartment of Physiology and Pathophysiology, Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0W2, CanadaDepartment of Human Anatomy and Cell Science, The Children’s Hospital Research Institute of Manitoba (CHRIM), Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0W2, CanadaDivision of Neuroscience, San Raffaele Scientific Institute, San Raffaele University, 20132 Milan, ItalyDepartment of Human Anatomy and Cell Science, The Children’s Hospital Research Institute of Manitoba (CHRIM), Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0W2, CanadaLysosomal acid phosphatase 2 (<i>Acp2</i>) mutant mice (naked-ataxia, <i>nax</i>) have a severe cerebellar cortex defect with a striking reduction in the number of granule cells. Using a combination of in vivo and in vitro immunohistochemistry, Western blotting, BrdU assays, and RT-qPCR, we show downregulation of MYCN and dysregulation of the SHH signaling pathway in the <i>nax</i> cerebellum. MYCN protein expression is significantly reduced at P10, but not at the peak of proliferation at around P6 when the number of granule cells is strikingly reduced in the <i>nax</i> cerebellum. Despite the significant role of the SHH–MycN pathway in granule cell proliferation, our study suggests that a broader molecular pathway and additional mechanisms regulating granule cell development during the clonal expansion period are impaired in the <i>nax</i> cerebellum. In particular, our results indicate that downregulation of the protein synthesis machinery may contribute to the reduced number of granule cells in the <i>nax</i> cerebellum.https://www.mdpi.com/1422-0067/22/6/2994granule cellsSHHMYCNcerebellummice<i>nax</i> |
| spellingShingle | Xiaodan Jiao Maryam Rahimi Balaei Ejlal Abu-El-Rub Filippo Casoni Hassan Pezeshgi Modarres Sanjiv Dhingra Jiming Kong Giacomo G. Consalez Hassan Marzban Reduced Granule Cell Proliferation and Molecular Dysregulation in the Cerebellum of Lysosomal Acid Phosphatase 2 (ACP2) Mutant Mice International Journal of Molecular Sciences granule cells SHH MYCN cerebellum mice <i>nax</i> |
| title | Reduced Granule Cell Proliferation and Molecular Dysregulation in the Cerebellum of Lysosomal Acid Phosphatase 2 (ACP2) Mutant Mice |
| title_full | Reduced Granule Cell Proliferation and Molecular Dysregulation in the Cerebellum of Lysosomal Acid Phosphatase 2 (ACP2) Mutant Mice |
| title_fullStr | Reduced Granule Cell Proliferation and Molecular Dysregulation in the Cerebellum of Lysosomal Acid Phosphatase 2 (ACP2) Mutant Mice |
| title_full_unstemmed | Reduced Granule Cell Proliferation and Molecular Dysregulation in the Cerebellum of Lysosomal Acid Phosphatase 2 (ACP2) Mutant Mice |
| title_short | Reduced Granule Cell Proliferation and Molecular Dysregulation in the Cerebellum of Lysosomal Acid Phosphatase 2 (ACP2) Mutant Mice |
| title_sort | reduced granule cell proliferation and molecular dysregulation in the cerebellum of lysosomal acid phosphatase 2 acp2 mutant mice |
| topic | granule cells SHH MYCN cerebellum mice <i>nax</i> |
| url | https://www.mdpi.com/1422-0067/22/6/2994 |
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