Mutations in the beta-Tubulin Gene TUBB5 Cause Microcephaly with Structural Brain Abnormalities
CELL REPORTS
Authors: Breuss, Martin; Heng, Julian Ik-Tsen; Poirier, Karine; Tian, Guoling; Jaglin, Xavier Hubert; Qu, Zhengdong; Braun, Andreas; Gstrein, Thomas; Ngo, Linh; Haas, Matilda; Bahi-Buisson, Nadia; Moutard, Marie-Laure; Passemard, Sandrine; Verloes, Alain; Gressens, Pierre; Xie, Yunli; Robson, Kathryn J. H.; Rani, Deepa Selvi; Thangaraj, Kumarasamy; Clausen, Tim; Chelly, Jamel; Cowan, Nicholas Justin; Keays, David Anthony
Abstract
The formation of the mammalian cortex requires the generation, migration, and differentiation of neurons. The vital role that the microtubule cytoskeleton plays in these cellular processes is reflected by the discovery that mutations in various tubulin isotypes cause different neurodevelopmental diseases, including lissencephaly (TUBA1A), polymicrogyria (TUBA1A, TUBB2B, TUBB3), and an ocular motility disorder (TUBB3). Here, we show that Tubb5 is expressed in neurogenic progenitors in the mouse and that its depletion in vivo perturbs the cell cycle of progenitors and alters the position of migrating neurons. We report the occurrence of three microcephalic patients with structural brain abnormalities harboring de novo mutations in TUBB5 (M299V, V353I, and E401K). These mutant proteins, which affect the chaperone-dependent assembly of tubulin heterodimers in different ways, disrupt neurogenic division and/or migration in vivo. Our results provide insight into the functional repertoire of the tubulin gene family, specifically implicating TUBB5 in embryonic neurogenesis and microcephaly.
Neuronal-Specific TUBB3 Is Not Required for Normal Neuronal Function but Is Essential for Timely Axon Regeneration
CELL REPORTS
Authors: Latremoliere, Alban; Cheng, Long; DeLisle, Michelle; Wu, Chen; Chew, Sheena; Hutchinson, Elizabeth B.; Sheridan, Andrew; Alexandre, Chloe; Latremoliere, Frederic; Sheu, Shu-Hsien; Golidy, Sara; Omura, Takao; Huebner, Eric A.; Fan, Yanjie; Whitman, Mary C.; Nguyen, Elaine; Hermawan, Crystal; Pierpaoli, Carlo; Tischfield, Max A.; Woolf, Clifford J.; Engle, Elizabeth C.
Abstract
We generated a knockout mouse for the neuronal-specific beta-tubulin isoform Tubb3 to investigate its role in nervous system formation and maintenance. Tubb3(-/)(-) mice have no detectable neurobehavioral or neuropathological deficits, and upregulation of mRNA and protein of the remaining beta-tubulin isotypes results in equivalent total beta-tubulin levels in Tubb3(-/-) and wild-type mice. Despite similar levels of total beta-tubulin, adult dorsal root ganglia lacking TUBB3 have decreased growth cone microtubule dynamics and a decreased neurite outgrowth rate of 22% in vitro and in vivo. The effect of the 22% slower growth rate is exacerbated for sensory recovery, where fibers must reinnervate the full volume of the skin to recover touch function. Overall, these data reveal that, while TUBB3 is not required for formation of the nervous system, it has a specific role in the rate of peripheral axon regeneration that cannot be replaced by other beta-tubulins.
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