The goal of this project is to understand the mechanisms that regulate maintenance of meiotic cohesion during prophase I. In humans, female meiosis is especially error-prone and the incidence of chromosome segregation errors increases dramatically as women age. Sister-chromatid cohesion holds sisters together from the time of their synthesis until they segregate to opposite poles and is therefore essential for accurate chromosome segregation during mitosis and meiosis. In addition, meiotic cohesion along the arms of sister chromatids provides an evolutionarily conserved mechanism to keep recombinant chromosomes associated until anaphase I and thereby ensure their accurate segregation during meiosis I. Because human oocytes undergo meiotic recombination during fetal development and remain suspended in a prolonged dictyate (diplotene) arrest until ovulation, the continuous association of homologous chromosomes demands that meiotic sister-chromatid cohesion be maintained for decades. Therefore, one of the factors that may contribute to age-dependent nondisjunction in human oocytes is deterioration of meiotic cohesion with age. Using Drosophila as a model system, we have tested this hypothesis and our recent work supports the model that as oocytes age, normal meiotic cohesion weakens during prophase I and this leads to increased nondisjunction of recombinant chromosomes. Despite its essential role, little is known about the mechanisms that ensure the maintenance of cohesion during meiotic prophase I or those that contribute to its demise. The experiments outlined in this proposal focus on these two fundamental issues.
Our specific aims are to: 1) Test the hypothesis that re-establishment of cohesion during prophase I is required for chiasma maintenance;2) Investigate the role of chromatin modifiers/remodelers in the regulation of meiotic sister- chromatid cohesion during prophase I;and 3) Test the hypothesis that oxidative damage contributes to loss of meiotic cohesion. In many respects, Drosophila is an ideal organism to investigate the mechanisms that control cohesion maintenance during meiotic prophase in metazoans and the genetic and cytological tools we have developed will be critical to address these questions. The information gained from the proposed experiments will significantly advance our understanding of the mechanisms that are required to maintain cohesion during meiotic prophase as well as yield valuable insight into the factors that cause meiotic cohesion to deteriorate with age. Given the conserved role of meiotic cohesion in holding recombinant chromosomes together until anaphase I, this work also promises to contribute to our understanding of why the fidelity of chromosome segregation decreases as human oocytes age.

Public Health Relevance

Meiosis is a specialized type of cell division that gives rise to eggs and sperm. In humans, errors during meiosis are the leading cause of birth defects and miscarriages. The experiments in this proposal are designed to elucidate the mechanisms that operate during normal meiosis, and to understand the defects that give rise to errors during human meiosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059354-12
Application #
8293369
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Janes, Daniel E
Project Start
2000-04-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
12
Fiscal Year
2012
Total Cost
$328,482
Indirect Cost
$120,582
Name
Dartmouth College
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Weng, Katherine A; Jeffreys, Charlotte A; Bickel, Sharon E (2014) Rejuvenation of meiotic cohesion in oocytes during prophase I is required for chiasma maintenance and accurate chromosome segregation. PLoS Genet 10:e1004607
Subramanian, Vijayalakshmi V; Bickel, Sharon E (2009) Heterochromatin-mediated association of achiasmate homologs declines with age when cohesion is compromised. Genetics 181:1207-18
Gause, Maria; Webber, Hayley A; Misulovin, Ziva et al. (2008) Functional links between Drosophila Nipped-B and cohesin in somatic and meiotic cells. Chromosoma 117:51-66
Page, Scott L; Khetani, Radhika S; Lake, Cathleen M et al. (2008) Corona is required for higher-order assembly of transverse filaments into full-length synaptonemal complex in Drosophila oocytes. PLoS Genet 4:e1000194
Subramanian, Vijayalakshmi V; Bickel, Sharon E (2008) Aging predisposes oocytes to meiotic nondisjunction when the cohesin subunit SMC1 is reduced. PLoS Genet 4:e1000263
Khetani, Radhika S; Bickel, Sharon E (2007) Regulation of meiotic cohesion and chromosome core morphogenesis during pachytene in Drosophila oocytes. J Cell Sci 120:3123-37
Webber, Hayley A; Howard, Louisa; Bickel, Sharon E (2004) The cohesion protein ORD is required for homologue bias during meiotic recombination. J Cell Biol 164:819-29
Balicky, Eric M; Young, Lynn; Orr-Weaver, Terry L et al. (2004) A proposed role for the Polycomb group protein dRING in meiotic sister-chromatid cohesion. Chromosoma 112:231-9
Jeffreys, Charlotte A; Burrage, Peter S; Bickel, Sharon E (2003) A model system for increased meiotic nondisjunction in older oocytes. Curr Biol 13:498-503
Bickel, Sharon E; Orr-Weaver, Terry L; Balicky, Eric M (2002) The sister-chromatid cohesion protein ORD is required for chiasma maintenance in Drosophila oocytes. Curr Biol 12:925-9

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