Molecular Glue controls Chromosome Segregation in Oocytes

November 25, 2013

Most trisomic pregnancies arise as a consequence of chromosome missegregation in egg precursor cells called oocytes. Austrian researchers at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences (ÖAW) aim to understand the molecular causes of female age-dependent chromosome missegregation in oocytes. They have now discovered that a “molecular glue” called cohesin plays an important role in proper functioning of checkpoint control, ensuring correct chromosome segregation and production of euploid eggs.

highly aneuploid mouse egg in which all sister chromatid cohesion has been inactivated by TEV protease cleavage of cohesin. The chromosomes are marked iby H2B-mCherry (red) and kinetochores are marked by EGFP-CenpB (green).

Portrait Kikue Tachibana-Konwalski

The spindle assembly checkpoint (SAC) is a surveillance mechanism that delays cell division until all chromosomes have attached to the spindle poles. If this mechanism is impaired in oocytes, it can result in chromosome missegregation and production of aneuploid fetuses, leading to abnormalities like Down’s syndrome (trisomy 21), Edward’s syndrome (trisomy 18) or Klinefelter’s syndrome (XXY). The IMBA researcher Kikue Tachibana-Konwalski and her team together with collaborators from the University of Oxford have now discovered that the proper functioning of the SAC in mammalian oocytes depends on the “molecular glue” called cohesin.

Cohesin is essential to hold replicated chromosomes together.  Using molecular “scissors” in the form of TEV protease, the researchers inactivated cohesin to generate chromosomes that cannot bi-orient on the spindle and therefore would be expected to activate a checkpoint response and trigger a cell cycle arrest.  Instead, they found that oocytes in which cohesin has been destroyed still divide and produce highly aneuploid eggs.  Therefore, cohesin is required for a robust SAC in oocytes. This has important implications for ageing oocytes, where cohesin deterioration will compromise the SAC, leading to chromosome segregation errors.

 

Original publication in “Current Biology”: “Spindle Assembly Checkpoint of Oocytes Depends on a Kinetochore Structure Determined by Cohesin in Meiosis I”