In utero gene therapy rescues microcephaly caused by Pqbp1-hypofunction in neural stem progenitor cells
| Autor: | Suzanna G.M. Frints, Corrado Romano, Erich E. Wanker, Charles E. Schwartz, Mikio Hoshino, Takeshi Kawauchi, Marius Sudol, Yoshiho Ikeuchi, Teppei Shimamura, Xigui Chen, Kyota Fujita, Tina Rich, Satoru Miyano, Hidenori Homma, Chisato Yoshida, Azad Bonni, Seiya Imoto, Hikaru Ito, Hiroki Shiwaku, Ute Fischer, Hong Luo, Hitoshi Okazawa, Vera M. Kalscheuer, Luciana Musante, Anup Arumughan, Fumio Matsuzaki, Shin-ichi Muramatsu |
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| Přispěvatelé: | Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - Oncology, RS: GROW - R4 - Reproductive and Perinatal Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Programmed cell death Microcephaly Neurogenesis Cell Apoptosis Biology Adenoviridae Nestin Mice Cellular and Molecular Neuroscience Neural Stem Cells medicine Animals Humans Apc4 Subunit Anaphase-Promoting Complex-Cyclosome Progenitor cell Molecular Biology Mitosis Cell Proliferation Mice Knockout Cell Cycle Brain Nuclear Proteins Genetic Therapy Cell cycle Embryo Mammalian Synapsins medicine.disease 3. Good health Cell biology DNA-Binding Proteins Disease Models Animal Psychiatry and Mental health medicine.anatomical_structure Female Original Article Stem cell Carrier Proteins Function and Dysfunction of the Nervous System Cell Adhesion Molecules Neuroscience |
| Zdroj: | Molecular Psychiatry Molecular Psychiatry, 20(4), 459-471. Nature Publishing Group |
| ISSN: | 1359-4184 |
| Popis: | Human mutations in PQBP1, a molecule involved in transcription and splicing, result in a reduced but architecturally normal brain. Examination of a conditional Pqbp1-knockout (cKO) mouse with microcephaly failed to reveal either abnormal centrosomes or mitotic spindles, increased neurogenesis from the neural stem progenitor cell (NSPC) pool or increased cell death in vivo. Instead, we observed an increase in the length of the cell cycle, particularly for the M phase in NSPCs. Corresponding to the developmental expression of Pqbp1, the stem cell pool in vivo was decreased at E10 and remained at a low level during neurogenesis (E15) in Pqbp1-cKO mice. The expression profiles of NSPCs derived from the cKO mouse revealed significant changes in gene groups that control the M phase, including anaphase-promoting complex genes, via aberrant transcription and RNA splicing. Exogenous Apc4, a hub protein in the network of affected genes, recovered the cell cycle, proliferation, and cell phenotypes of NSPCs caused by Pqbp1-cKO. These data reveal a mechanism of brain size control based on the simple reduction of the NSPC pool by cell cycle time elongation. Finally, we demonstrated that in utero gene therapy for Pqbp1-cKO mice by intraperitoneal injection of the PQBP1-AAV vector at E10 successfully rescued microcephaly with preserved cortical structures and improved behavioral abnormalities in Pqbp1-cKO mice, opening a new strategy for treating this intractable developmental disorder.Molecular Psychiatry advance online publication, 29 July 2014; doi:10.1038/mp.2014.69. |
| Databáze: | OpenAIRE |
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