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  In utero gene therapy rescues microcephaly caused by Pqbp1-hypofunction in neural stem progenitor cells

Ito, H., Shiwaku, H., Yoshida, C., Homma, H., Luo, H., Chen, X., et al. (2015). In utero gene therapy rescues microcephaly caused by Pqbp1-hypofunction in neural stem progenitor cells. Molecular Psychiatry, 20(4), 459-471. doi:10.1038/mp.2014.69.

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© 2014 Macmillan Publishers Limited
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Ito, H., Author
Shiwaku, H., Author
Yoshida, C., Author
Homma, H., Author
Luo, H., Author
Chen, X., Author
Fujita, K., Author
Musante, L.1, Author           
Fischer, U.2, Author           
Frints, S. G., Author
Romano, C., Author
Ikeuchi, Y., Author
Shimamura, T., Author
Imoto, S., Author
Miyano, S., Author
Muramatsu, S. I., Author
Kawauchi, T., Author
Hoshino, M., Author
Sudol, M., Author
Arumughan, A., Author
Wanker, E. E., AuthorRich, T., AuthorSchwartz, C., AuthorMatsuzaki, F., AuthorBonni, A., AuthorKalscheuer, V. M.2, 3, Author           Okazawa, H., Author more..
Affiliations:
1Familial Cognitive Disorders (Luciana Musante), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479644              
2Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479642              
3Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479642              

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 Abstract: 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.

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Language(s): eng - English
 Dates: 2014-07-292015-04
 Publication Status: Issued
 Pages: 13
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/mp.2014.69
ISSN: 1476-5578 (Electronic)1359-4184 (Print)
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Title: Molecular Psychiatry
Source Genre: Journal
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Publ. Info: Houndmills, Hampshire, UK : Stockton Press
Pages: - Volume / Issue: 20 (4) Sequence Number: - Start / End Page: 459 - 471 Identifier: ISSN: 1359-4184
CoNE: https://pure.mpg.de/cone/journals/resource/954925619131