Gametogenesis is central to sexual reproduction. It is defined as the developmental program that leads to the formation of specialized germ cells and is frequently associated with a unique cell division called meiosis. Defects in gametogenesis and meiosis have a profound impact on human health. Defects in gametogenesis lead to infertility;Chromosome mis-segregation during meiosis is the leading cause of miscarriages and mental retardation in humans. Determining the causes of gametogenesis failure and meiotic chromosome mis-segregation is thus vital for understanding the principles underlying infertility and disabilities such as Down's Syndrome. The long-term goal of our studies is to determine the molecular mechanisms that induce the germ cell fate and that transform the canonical mitotic cell cycle into the unique meiotic cell division program. Our previous studies in budding yeast indicate that meiosis-specific factors act on the canonical cell cycle machinery, the cyclin-dependent kinases (CDKs), to bring about gametogenesis and the accompanying unique cell division. Here we propose to study the mechanistic basis of this transformation.
In Specific Aim 1 we will determine the mechanisms that induce gametogenesis. This cell fate transition is poorly understood in all eukaryotes yet the process is so critical for sexual reproduction. We will study germ cell fate specification in budding yeast where this cell fate is induced by the transcription factor Ime1. Previous work demonstrated that all germ cell fate-inducing signals converge on the promoter of IME1. We will investigate how signal integration occurs at the IME1 promoter by identifying the elements in the IME1 promoter that mediate signal integration and by characterizing the regulatory mechanisms controlling IME1 expression.
In Specific Aim 2 we will examine the mechanisms that transform the canonical mitotic cell division into the unique gametogenesis-accompanying meiotic division. We will investigate how inappropriate premature expression of a CDK subtype, Clb3-CDK, suppresses meiosis I and instead induces a mitotic division.
In Specific Aim 3 we will study the molecular mechanisms that ensure that Clb3-CDKs are not expressed prematurely. Our previous studies showed that inhibition of translation restricts Clb3 expression to meiosis II. We will now determine the molecular mechanisms governing meiosis I translational inhibition. The mechanisms governing gametogenesis and meiosis are highly conserved from yeast to human. Thus, as with many other studies, the regulatory processes discovered and characterized in yeast will likely guide the way for studies in higher eukaryotes including human.

Public Health Relevance

Gametogenesis is central to sexual reproduction. It is defined as the developmental pathway that leads to the formation of specialized germ cells and is frequently associated with a unique cell division called meiosis. Defects in gametogenesis and meiosis have a profound impact on human health. They lead to infertility and birth defects. Gametogenesis failure is a main cause of infertility in humans;chromosome mis-segregation during meiosis is the leading cause of miscarriages and mental retardation in humans. Determining the causes of gametogenesis failure and meiotic chromosome mis-segregation is thus vital for understanding the principles underlying infertility and developmental disabilities such as Down's Syndrome.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01GM062207-13
Application #
8626117
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Hamlet, Michelle R
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Berchowitz, Luke E; Kabachinski, Greg; Walker, Margaret R et al. (2015) Regulated Formation of an Amyloid-like Translational Repressor Governs Gametogenesis. Cell 163:406-18
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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