An increase in aneuploidy is a major cause for the marked decline in human female fertility commencing 35 years-of-age;the incidence of aneuploidy in eggs from women increases to 35% around 40 years-of-age, and is likely to be even higher because aneuploidy leading to a spontaneous abortion is frequently not recognized. Aneuploidy is a leading cause of pregnancy loss, and when development goes to term, an aggravating source of developmental disabilities and mental retardation. Most aneuplodies associated with increased maternal age are due to non-disjunction and meiotic errors that occur during meiosis. Remarkably, the underlying molecular mechanisms that lead to the age-associated increase in aneuploidy are poorly understood. Results of our previous studies suggest that defects in the spindle assembly checkpoint (SAC) and kinetochore function are likely causes for the age-associated increase in aneuploidy. The SAC is one pathway that prevents segregation errors by blocking the onset of anaphase until all chromosomes make proper attachments to the spindle. Using mouse as a model system and imaging of live individual oocytes, Specific Aim 1 will test the hypothesis that the robustness of the SAC in oocytes decreases with age . Another process that prevents errors is regulation of connections between kinetochores and spindle microtubules that results in a spindle with chromosomes correctly attached. Our expression profiling also reveals changes in expression of kinetochore proteins involved in chromosome congression.
Specific Aim 2 will examine chromosome congression and molecular mechanisms that underlie correct spindle microtubule-kinetochore attachment, and test the hypothesis that these mechanisms are compromised in oocytes obtained from old females.
Specific Aim 3 will test whether specific centromere and kinetochore proteins identified from our expression profiling studies are required for accurate chromosome segregation during MI. Results of experiments proposed in this application will provide a plethora of information regarding molecular bases that underlie the age-associated increase in the incidence of aneuploidy, as well as basic mechanisms required for accurate chromosome segregation. Such findings may suggest experimental interventions that could alleviate the propensity of oocytes obtained from older women to become aneuploid.

Public Health Relevance

The proposed studies will provide new information regarding molecular mechanisms that underlie the maternal age-associated increase in aneuploidy. The results of these studies will likely impact on the treatment of human infertility and assisted reproduction technologies.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD058730-05
Application #
8468186
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Taymans, Susan
Project Start
2009-08-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$299,440
Indirect Cost
$112,290
Name
University of Pennsylvania
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Chiang, Teresa; Lampson, Michael A (2013) Counting chromosomes in intact eggs. Methods Mol Biol 957:249-53
Davydenko, Olga; Schultz, Richard M; Lampson, Michael A (2013) Increased CDK1 activity determines the timing of kinetochore-microtubule attachments in meiosis I. J Cell Biol 202:221-9
Chiang, Teresa; Schultz, Richard M; Lampson, Michael A (2012) Meiotic origins of maternal age-related aneuploidy. Biol Reprod 86:1-7
Chiang, Teresa; Schultz, Richard M; Lampson, Michael A (2011) Age-dependent susceptibility of chromosome cohesion to premature separase activation in mouse oocytes. Biol Reprod 85:1279-83
Chiang, Teresa; Duncan, Francesca E; Schindler, Karen et al. (2010) Evidence that weakened centromere cohesion is a leading cause of age-related aneuploidy in oocytes. Curr Biol 20:1522-8
Duncan, Francesca E; Chiang, Teresa; Schultz, Richard M et al. (2009) Evidence that a defective spindle assembly checkpoint is not the primary cause of maternal age-associated aneuploidy in mouse eggs. Biol Reprod 81:768-76