Resumen de Relevancia Funcional de Tpx2 en mamíferos

Cristina Aguirre Portolés

• The establishment of a bipolar spindle is crucial to ensure the genome integrity in the daughter cells resulting from cell division. 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. These 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. We also demonstrate that Tpx2 is essential during the adulthood in mammals. Loss of Tpx2 expression led to acute liver failure causing premature death of the mice. We also describe here a new role of Tpx2 in regulating mitogenic pathways through the control of protein trafficking from the cytoplasm to the nucleus.

  Together, these results reveal critical roles for Tpx2 during the cell cycle in physiological conditions and in tumors and shed light on new functions that Tpx2 exerts out of mitosis.