Abstract
Tpx2 is a microtubule-associated protein that activates the cell-cycle kinase Aurora A and regulates the mitotic spindle. Overexpression of Tpx2 is associated with the development of different human tumors and strongly correlates with chromosomal instability. By analyzing a conditional null mutation in the mouse Tpx2 gene, we show here that Tpx2 expression is essential for spindle function and chromosome segregation in the mouse embryo. Conditional genetic ablation of Tpx2 in primary cultures resulted in deficient microtubule nucleation from DNA and aberrant spindles during prometaphase. These cells eventually exited from mitosis without chromosome segregation. In addition, Tpx2 haploinsufficiency led to the accumulation of aneuploidies in vivo and increased susceptibility to spontaneous lymphomas and lung tumors. Together, our findings indicate that Tpx2 is essential for maintaining genomic stability through its role in spindle regulation. Subtle changes in Tpx2 expression may favor tumor development in vivo.
Highlights
Formation of a proper bipolar spindle is an essential process required for accurate chromosome segregation
No homozygous Tpx2À/À mutant was born from intercrosses between Tpx2þ/À mice and, null embryos were absent between embryonic day (E)8.5 and E17.5 (Fig. 1B), suggesting early embryonic lethality in the absence of Tpx2
We report in this article that lack of Tpx2 causes early embryonic lethality during preimplantational development in the mouse
Summary
Formation of a proper bipolar spindle is an essential process required for accurate chromosome segregation. This dynamic microtubule-based structure is responsible for chromosomal movements that ensure the equal distribution of a single, complete complement of the genome into 2 daughter cells. Chromatin-driven microtubule nucleation and organization depends on a gradient of Ran-GTP known to promote microtubule nucleation and stabilization surrounding the chromosomes [1]. Tpx is one of the best studied factors regulated by the Ran-GTP gradient during mitosis. Once released from its inhibitory complex with importin-a, Tpx is able to promote microtubule nucleation from the chromatin, both in Xenopus extracts and in human cells [3,4,5]. The N-terminal domain of Tpx interacts with Aurora A protecting the Thr288 in the T-loop of the kinase from
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