Abstract
Proper chromosome segregation is essential to avoid aneuploidy, yet this process fails with increasing age in mammalian oocytes. Here we report a role for the scarcely described protein CENP-V in oocyte spindle formation and chromosome segregation. We show that depending on the oocyte maturation state, CENP-V localizes to centromeres, to microtubule organizing centers, and to spindle microtubules. We find that Cenp-V−/− oocytes feature severe deficiencies, including metaphase I arrest, strongly reduced polar body extrusion, increased numbers of mis-aligned chromosomes and aneuploidy, multipolar spindles, unfocused spindle poles and loss of kinetochore spindle fibres. We also show that CENP-V protein binds, diffuses along, and bundles microtubules in vitro. The spindle assembly checkpoint arrests about half of metaphase I Cenp-V−/− oocytes from young adults only. This finding suggests checkpoint weakening in ageing oocytes, which mature despite carrying mis-aligned chromosomes. Thus, CENP-V is a microtubule bundling protein crucial to faithful oocyte meiosis, and Cenp-V−/− oocytes reveal age-dependent weakening of the spindle assembly checkpoint.
Highlights
Proper chromosome segregation is essential to avoid aneuploidy, yet this process fails with increasing age in mammalian oocytes
This pattern is similar to that seen in spermatocyte prophase I, where CENP-V localized to the centromere region and external to the centromere protein CENP-A from the pachytene stage onwards, similar to what has been described for mitotic HeLa cells[20]
Here we report that the poorly described protein CENP-V crucially contributes to mammalian meiosis I and II
Summary
Proper chromosome segregation is essential to avoid aneuploidy, yet this process fails with increasing age in mammalian oocytes. Mammalian oogenesis is burdened with comparably high rates of failures that may result in chromosome missegregation and aneuploidy (for reviews see[1,2,3,4,5,6,7,8,9]) These errors happen during oocyte meiosis, which includes a very prolonged period of arrest, and increase with advancing age. Erroneous attachment of microtubules to the kinetochores may lead to mis-segregation if not corrected during a spindle assembly checkpoint (SAC) mediated arrest. It appears as if the control mechanisms provided by the SAC weaken with advancing age this has not yet been clearly demonstrated. We describe CENP-V as an important regulator of oocyte microtubulekinetochore associations and chromosome segregation, whose absence causes age-dependent failure of the SAC and aneuploidy
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