Mutations in the murine homologue of TUBB5 cause microcephaly by perturbing cell cycle progression and inducing p53-associated apoptosis.
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.
['Breuss|Martin|M|', 'Fritz|Tanja|T|', 'Gstrein|Thomas|T|', 'Chan|Kelvin|K|', 'Ushakova|Lyubov|L|', 'Yu|Nuo|N|', 'Vonberg|Frederick W|FW|', 'Werner|Barbara|B|', 'Elling|Ulrich|U|', 'Keays|David A|DA|']
D000818:Animals D017209:Apoptosis D001921:Brain D002453:Cell Cycle D002454:Cell Differentiation D004195:Disease Models, Animal D004622:Embryo, Mammalian D055879:Gene Knock-In Techniques D008279:Magnetic Resonance Imaging D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008831:Microcephaly D008870:Microtubules D058953:Neural Stem Cells D055748:SOXB1 Transcription Factors D008941:Spindle Apparatus D013234:Stem Cells D014404:Tubulin D016159:Tumor Suppressor Protein p53
Microcephaly Apoptosis Tubulin Trp53