Aneuploidy is the leading cause of miscarriages and mental retardation in humans. Determining the causes of meiotic chromosome mis-segregation is thus vital for understanding the principles underlying Down's Syndrome and infertility. The long- term goal of our studies is to define the mechanisms that prevent chromosome mis-segregation and thus aneuploidy during meiosis. Meiosis is a specialized cell division during which a single DNA replication phase is followed by two consecutive chromosome segregation phases (meiosis I and meiosis II). Meiosis-specific factors act on the cyclin-dependent kinase (CDK) Cdc28 associated with the six Clb cyclins (Clb-CDKs) to bring about the unique meiotic cell division program. This grant has two goals. (1) We want to characterize how Clb-CDKs control meiosis. (2) We want to characterize the changes that occur on CDKs and its regulators during meiosis and to identify the meiosis-specific regulators that cause these changes.
In Specific Aim 1 we will determine the mechanisms that prevent Clb1-CDKs from being active during meiosis II and examine the importance of this regulation.
In Specific Aim 2 we will investigate how translation of the cyclin CLB3 is controlled. Inhibition of CLB3 translation is essential for meiosis I chromosome segregation. Thus, understanding how CLB3 translation is controlled and how CLB3 inhibits meiosis I is essential to understand how a meiosis I chromosome segregation pattern is established.
In Specific Aim 3 we will determine how CLB3 inhibits meiosis I chromosome segregation. Since the basic cell division machinery is highly conserved from yeast to human and given that most of the factors described in this proposal have also been shown to control meiosis in mammals, it is likely that the processes governing meiosis will also be conserved across species. Thus, as with many other cell cycle studies, the regulatory processes discovered and characterized in yeast will likely guide the way for studies in higher eukaryotes including human. Public Health Relevance: Aneuploidy generated during meiosis is the leading cause of mental retardation and miscarriages in humans. Determining the molecular mechanisms governing meiotic chromosome segregation and the surveillance pathways that ensure that gamete formation occurs with accuracy is thus vital for understanding the principles underlying chromosome mis-segregation leading to Down's Syndrome and infertility. The long-term goal of our studies is to define the mechanisms that control meiotic chromosome segregation and gamete formation at the molecular level.

Public Health Relevance

Aneuploidy generated during meiosis is the leading cause of mental retardation and miscarriages in humans. Determining the molecular mechanisms governing meiotic chromosome segregation and the surveillance pathways that ensure that gamete formation occurs with accuracy is thus vital for understanding the principles underlying chromosome mis-segregation leading to Down's Syndrome and infertility. The long-term goal of our studies is to define the mechanisms that control meiotic chromosome segregation and gamete formation at the molecular level.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062207-10
Application #
8004059
Study Section
Special Emphasis Panel (ZRG1-CB-J (02))
Program Officer
Hamlet, Michelle R
Project Start
2001-03-01
Project End
2013-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
10
Fiscal Year
2011
Total Cost
$272,266
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
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Berchowitz, Luke E; Gajadhar, Aaron S; van Werven, Folkert J et al. (2013) A developmentally regulated translational control pathway establishes the meiotic chromosome segregation pattern. Genes Dev 27:2147-63
Attner, Michelle A; Miller, Matthew P; Ee, Ly-sha et al. (2013) Polo kinase Cdc5 is a central regulator of meiosis I. Proc Natl Acad Sci U S A 110:14278-83
Miller, Matthew P; Amon, Angelika; Ünal, Elçin (2013) Meiosis I: when chromosomes undergo extreme makeover. Curr Opin Cell Biol 25:687-96
van Werven, Folkert J; Neuert, Gregor; Hendrick, Natalie et al. (2012) Transcription of two long noncoding RNAs mediates mating-type control of gametogenesis in budding yeast. Cell 150:1170-81
Attner, Michelle A; Amon, Angelika (2012) Control of the mitotic exit network during meiosis. Mol Biol Cell 23:3122-32
Miller, Matthew P; Unal, Elçin; Brar, Gloria A et al. (2012) Meiosis I chromosome segregation is established through regulation of microtubule-kinetochore interactions. Elife 1:e00117
Ãœnal, E; Amon, A (2011) Gamete formation resets the aging clock in yeast. Cold Spring Harb Symp Quant Biol 76:73-80
van Werven, Folkert J; Amon, Angelika (2011) Regulation of entry into gametogenesis. Philos Trans R Soc Lond B Biol Sci 366:3521-31
Unal, Elçin; Kinde, Benyam; Amon, Angelika (2011) Gametogenesis eliminates age-induced cellular damage and resets life span in yeast. Science 332:1554-7

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