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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 knockin; and a conditional knockout animal. We report that 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 knockin 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.<\/jats:p>","DOI":"10.1242\/dev.131516","type":"journal-article","created":{"date-parts":[[2016,2,23]],"date-time":"2016-02-23T03:24:13Z","timestamp":1456197853000},"source":"Crossref","is-referenced-by-count":27,"title":["Mutations in the murine homologue of<i>TUBB5<\/i>cause microcephaly by perturbing cell cycle progression and inducing p53 associated apoptosis"],"prefix":"10.1242","author":[{"given":"Martin","family":"Breuss","sequence":"first","affiliation":[{"name":"Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Fritz","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Gstrein","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelvin","family":"Chan","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria"},{"name":"Medical Scientist Training Program, Stony Brook University Medical Center, Stony Brook, New York 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyubov","family":"Ushakova","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuo","family":"Yu","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick W","family":"Vonberg","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria"},{"name":"Wellcome Trust Centre for Human Genetics, Roosevelt Drive Oxford, OX3 7BN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Werner","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Elling","sequence":"additional","affiliation":[{"name":"Institute for Molecular Biotechnology (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna 1030, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Keays","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, Vienna 1030, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042608470844600_DEV131516C1","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/S0962-8924(00)01880-8","article-title":"Chromosomal passengers and the (aurora) ABCs of mitosis","volume":"11","author":"Adams","year":"2001","journal-title":"Trends Cell Biol."},{"key":"2021042608470844600_DEV131516C2","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1002\/ajmg.c.31397","article-title":"Congenital microcephaly","volume":"166","author":"Alcantara","year":"2014","journal-title":"Am. 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