Ngo Linh, Haas Matilda, Qu Zhengdong, Li Shan Shan, Zenker Jennifer, Teng Kathleen Sue Lyn, Gunnersen Jenny Margaret, Breuss Martin, Habgood Mark, Keays David Anthony, Heng Julian Ik-Tsen
EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
The Anatomy and Neuroscience Department, University of Melbourne, Parkville, VIC 3010, Australia.
Hum Mol Genet. 2014 Oct 1;23(19):5147-58. doi: 10.1093/hmg/ddu238. Epub 2014 May 15.
The microtubule cytoskeleton is critical for the generation and maturation of neurons in the developing mammalian nervous system. We have previously shown that mutations in the β-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities in humans. While it is known that TUBB5 is necessary for the proper generation and migration of neurons, little is understood of the role it plays in neuronal differentiation and connectivity. Here, we report that perturbations to TUBB5 disrupt the morphology of cortical neurons, their neuronal complexity, axonal outgrowth, as well as the density and shape of dendritic spines in the postnatal murine cortex. The features we describe are consistent with defects in synaptic signaling. Cellular-based assays have revealed that TUBB5 substitutions have the capacity to alter the dynamic properties and polymerization rates of the microtubule cytoskeleton. Together, our studies show that TUBB5 is essential for neuronal differentiation and dendritic spine formation in vivo, providing insight into the underlying cellular pathology associated with TUBB5 disease states.
微管细胞骨架对于发育中的哺乳动物神经系统中神经元的产生和成熟至关重要。我们之前已经表明，β-微管蛋白基因TUBB5的突变会导致人类出现小头畸形并伴有脑部结构异常。虽然已知TUBB5对于神经元的正常产生和迁移是必需的，但对于它在神经元分化和连接中所起的作用却知之甚少。在这里，我们报告称，对TUBB5的干扰会破坏出生后小鼠皮质中皮质神经元的形态、神经元复杂性、轴突生长以及树突棘的密度和形状。我们所描述的这些特征与突触信号传导缺陷一致。基于细胞的实验表明，TUBB5替代物有能力改变微管细胞骨架的动态特性和聚合速率。总之，我们的研究表明TUBB5在体内对于神经元分化和树突棘形成至关重要，这为深入了解与TUBB5疾病状态相关的潜在细胞病理学提供了线索。
