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

H. Ito, H. Shiwaku, C. Yoshida, H. Homma, H. Luo, X. Chen, K. Fujita, L. Musante, U. Fischer, S. G.M. Frints, C. Romano, Y. Ikeuchi, T. Shimamura, S. Imoto, S. Miyano, S. I. Muramatsu, T. Kawauchi, M. Hoshino, M. Sudol, A. ArumughanE. E. Wanker, T. Rich, C. Schwartz, F. Matsuzaki, A. Bonni, V. M. Kalscheuer, H. Okazawa

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)459-471
Number of pages13
JournalMolecular psychiatry
Issue number4
StatePublished - Apr 2 2015

Bibliographical note

Funding Information:
This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas ‘Foundation of Synapse and Neurocircuit Pathology’ (22110001, 22110002), Strategic Research Program for Brain Sciences (SRPBS) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) (18390254), CREST from Japan Science and Technology Agency (JST) to HO, the Deutsche Forschungsgemeinschaft, SFB577 to VMK and HHR, research grants from the Department of Health, Pennsylvania, USA, RFA60707 and RFA09200903 to MS and NIH grant NS084393 to AB. We thank Drs Kazuhiko Tagawa, Takuya Tamura, Masaki Sone, Naoyuki Kataoka, Miho Soma, Koichi Tanaka, and Ms Tayoko Tajima (TMDU) for technical assistance and critical discussion. We appreciate the technical support of Drs Yoshiaki V Nishimura, Daijiro Konno, Shigeaki Kanatani and Kazunori Nakajima (Keio University), Mss Mami Terao and Mimi Adachi (Kyoto University), and critical advice from Dr Shigetaka Kitajima (TMDU) and continuous encouragement from Professor Ichiro Kanazawa (National Center for Neurology and Psychiatry).

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