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dc.contributor.authorIto, Hen_US
dc.contributor.authorShiwaku, Hen_US
dc.contributor.authorYoshida, Cen_US
dc.contributor.authorHomma, Hen_US
dc.contributor.authorLuo, Hen_US
dc.contributor.authorChen, Xen_US
dc.contributor.authorFujita, Ken_US
dc.contributor.authorMusante, Len_US
dc.contributor.authorFischer, Uen_US
dc.contributor.authorFrints, S G Men_US
dc.contributor.authorRomano, Cen_US
dc.contributor.authorIkeuchi, Yen_US
dc.contributor.authorShimamura, Ten_US
dc.contributor.authorImoto, Sen_US
dc.contributor.authorMiyano, Sen_US
dc.contributor.authorMuramatsu, S-ien_US
dc.contributor.authorKawauchi, Ten_US
dc.contributor.authorHoshino, Men_US
dc.contributor.authorSudol, Men_US
dc.contributor.authorArumughan, Aen_US
dc.contributor.authorWanker, E Een_US
dc.contributor.authorRich, Ten_US
dc.contributor.authorSchwartz, Cen_US
dc.contributor.authorMatsuzaki, Fen_US
dc.contributor.authorBonni, Aen_US
dc.contributor.authorKalscheuer, V Men_US
dc.contributor.authorOkazawa, Hen_US
dc.date.accessioned2015-05-04T15:27:35Z
dc.date.issued2015en_US
dc.identifier.citationIto, H., H. Shiwaku, C. Yoshida, H. Homma, H. Luo, X. Chen, K. Fujita, 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. http://dx.doi.org/10.1038/mp.2014.69.en
dc.identifier.issn1359-4184en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:15034961
dc.description.abstractHuman 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.en
dc.language.isoen_USen
dc.publisherNature Publishing Groupen
dc.relation.isversionofdoi:10.1038/mp.2014.69en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378255/pdf/en
dash.licenseLAAen_US
dc.titleIn utero gene therapy rescues microcephaly caused by Pqbp1-hypofunction in neural stem progenitor cellsen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalMolecular Psychiatryen
dc.date.available2015-05-04T15:27:35Z
dc.identifier.doi10.1038/mp.2014.69*
dash.authorsorderedfalse


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