title: In utero gene therapy rescues microcephaly caused by Pqbp1-hypofunction in neural stem progenitor cells.
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.
authors: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
authors: H
authors: H
authors: Ito
authors: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
authors: H
authors: H
authors: Shiwaku
authors: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
authors: C
authors: C
authors: Yoshida
authors: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
authors: H
authors: H
authors: Homma
authors: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
authors: H
authors: H
authors: Luo
authors: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
authors: X
authors: X
authors: Chen
authors: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
authors: K
authors: K
authors: Fujita
authors: Department of Human Molecular Genetics, Max-Planck Institute for Molecular Genetics, Berlin-Dahlem, Germany.
authors: L
authors: L
authors: Musante
authors: Department of Human Molecular Genetics, Max-Planck Institute for Molecular Genetics, Berlin-Dahlem, Germany.
authors: U
authors: U
authors: Fischer
authors: 1] Department of Clinical Genetics, University Hospital azM Maastricht, Maastricht, The Netherlands [2] School for Oncology and Developmental Biology, GROW, Maastricht University, Maastricht, The Netherlands.
authors: S G M
authors: SG
authors: Frints
authors: Unità Operativa Complessa di Pediatria e Genetica Medica, IRCCS Associazione Oasi Maria Santissima, Troina (Enna), Italy.
authors: C
authors: C
authors: Romano
authors: 1] Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO, USA [2] Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
authors: Y
authors: Y
authors: Ikeuchi
authors: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: T
authors: T
authors: Shimamura
authors: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: S
authors: S
authors: Imoto
authors: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: S
authors: S
authors: Miyano
authors: Department of Neurology, Jichi Medical University, Tochigi, Japan.
authors: S-i
authors: SI
authors: Muramatsu
authors: Department of Anatomy, Keio University School of Medicine, Tokyo, Japan.
authors: T
authors: 0000000286504474
authors: T
authors: Kawauchi
authors: Department of Biochemistry and Cellular Biology, National Center for Neurology and Psychiatry, Tokyo, Japan.
authors: M
authors: M
authors: Hoshino
authors: Laboratory of Signal Transduction and Proteomic Profiling, Weis Center for Research, Geisinger Clinic, Danville, PA, USA.
authors: M
authors: M
authors: Sudol
authors: Department of Neurogenetics, Max-Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
authors: A
authors: A
authors: Arumughan
authors: Department of Neurogenetics, Max-Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
authors: E E
authors: EE
authors: Wanker
authors: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
authors: T
authors: T
authors: Rich
authors: JC Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC, USA.
authors: C
authors: C
authors: Schwartz
authors: Laboratory for Cell Asymmetry, Center for Developmental Biology, RIKEN, Chuo-ku, Kobe, Japan.
authors: F
authors: F
authors: Matsuzaki
authors: 1] Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO, USA [2] Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
authors: A
authors: A
authors: Bonni
authors: Department of Human Molecular Genetics, Max-Planck Institute for Molecular Genetics, Berlin-Dahlem, Germany.
authors: V M
authors: VM
authors: Kalscheuer
authors: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
authors: H
authors: H
authors: Okazawa
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D064192:Apc4 Subunit, Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D001921:Brain / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology*; D055495:Neurogenesis; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D016704:Synapsins / Q000235:genetics / Q000378:metabolism
chemical_list: C577369:ANAPC4 protein, human; D064192:Apc4 Subunit, Anaphase-Promoting Complex-Cyclosome; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D064231:Nestin; D009687:Nuclear Proteins; C492272:Pqbp1 protein, mouse; D016704:Synapsins; C013065:cell aggregation factors