title: Mutations in the murine homologue of TUBB5 cause microcephaly by perturbing cell cycle progression and inducing p53-associated apoptosis.
abstract: Microtubules play a crucial role in the generation, migration and differentiation of nascent neurons in the developing vertebrate brain. Mutations in the constituents of microtubules, the tubulins, are known to cause an array of neurological disorders, including lissencephaly, polymicrogyria and microcephaly. In this study we explore the genetic and cellular mechanisms that cause TUBB5-associated microcephaly by exploiting two new mouse models: a conditional E401K knock-in, and a conditional knockout animal. These mice present with profound microcephaly due to a loss of upper-layer neurons that correlates with massive apoptosis and upregulation of p53. This phenotype is associated with a delay in cell cycle progression and ectopic DNA elements in progenitors, which is dependent on the dosage of functional Tubb5. Strikingly, we report ectopic Sox2-positive progenitors and defects in spindle orientation in our knock-in mouse line, which are absent in knockout animals. This work sheds light on the functional repertoire of Tubb5, reveals that the E401K mutation acts by a complex mechanism, and demonstrates that the cellular pathology driving TUBB5-associated microcephaly is cell death.
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Breuss
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria.
authors.forename: Tanja
authors.initials: T
authors.lastname: Fritz
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gstrein
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria Medical Scientist Training Program, Stony Brook University Medical Center, Stony Brook, NY 11794, USA.
authors.forename: Kelvin
authors.initials: K
authors.lastname: Chan
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria.
authors.forename: Lyubov
authors.initials: L
authors.lastname: Ushakova
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria.
authors.forename: Nuo
authors.initials: N
authors.lastname: Yu
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Vonberg
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Werner
authors.affiliation: Institute for Molecular Biotechnology (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna 1030, Austria.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Elling
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria david.keays@imp.ac.at.
authors.forename: David A
authors.initials: DA
authors.lastname: Keays
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001921:Brain / Q000002:abnormalities / Q000196:embryology; D002453:Cell Cycle / Q000235:genetics*; D002454:Cell Differentiation; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000196:embryology; D055879:Gene Knock-In Techniques; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics*; D008870:Microtubules / Q000235:genetics* / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D008941:Spindle Apparatus / Q000235:genetics; D013234:Stem Cells / Q000166:cytology; D014404:Tubulin / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C000598026:TUBB5 protein, mouse; D014404:Tubulin; D016159:Tumor Suppressor Protein p53
keywords: Apoptosis; Microcephaly; Trp53; Tubulin