Throughout the lifespan of a cell, a combination of transcriptional and post-transcriptional regulations control gene expression, particularly at the time of critical developmental decisions and during the cell cycle. This is especially true for the development of gametes. Indeed, many pivotal transitions required for the differentiation of these cells rely more on translational regulation of mRNA than on transcription. To overcome the technical hurdles inherent in the germ cell experimental model, we have developed novel strategies to investigate how translation is regulated in mouse oocytes. Monitoring the association of maternal mRNAs with ribosomes together with single oocyte translation assays has allowed us to view the translational landscape in oocytes during growth and maturation in ways previously not possible. By monitoring translation at a genome-wide level, we have identified a global switch in translation that occurs at the time of oocyte reentry into the meiotic cell cycle. Translation of mRNAs required for oocyte growth ceases, while translation of mRNA coding for cell cycle components is activated together with translation of components that will be necessary for embryo development. Using the translation of the critical cell cycle components Cyclin B1 and Cyclin B2 as a paradigm, we have demonstrated that translation defines some unique properties of the meiotic cell cycle. Here, we propose to extend these observations by exploring further how differential translation of maternal mRNAs is regulated during oocyte growth and maturation. The experiments are organized along three specific aims. With the first Specific Aim, we will investigate the intrinsic features of the 3'UTR of mRNAs translated at high levels during oocyte growth and quiescence. We will use novel strategies to identify functional elements in the 3' UTR of an mRNA including those present in the Cyclin B2 mRNA, and to understand how they contribute to translational control in vitro and in vivo. With the second Specific Aim, we will explore the biochemical properties of protein complexes that function as repressors of translation, including those involved in repression of CyclinB1 translation. In the last Specific Aim, we will investigate how repression of translation is triggered at the time of oocyte reentry into the cell cycle. We will establish links between translational repression and regulation of cell cycle components. In addition, we will explore the 3' UTR code that defines timely repression of translation and destabilization. The major outcome of these studies will be a better understanding of the mechanism of repression and activation of maternal mRNA during gamete development. These studies are significant because they will shed light on how mRNA translation is intimately involved in regulation of the cell cycle and how translational programs direct development.

Public Health Relevance

The regulation of gene expression is essential for normal cell function, and disruption of this process is often the cause of human diseases. Here, we propose to investigate one aspect of gene expression relatively underdeveloped compared to the mechanisms controlling genes transcription. How mRNA is translated into proteins is emerging as a complex and highly regulated function of the cell critical for most biological processes. We propose to investigate how translation of mRNA into proteins is regulated during the specialized meiotic cell cycle. A better understanding of how this program of translation is executed will provide insight into the mechanisms controlling cell division as well as the processes involved in gamete and embryo development. It will also provide new concepts useful in understanding the causes of chromosome abnormalities.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Carter, Anthony D
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University of California San Francisco
Obstetrics & Gynecology
Schools of Medicine
San Francisco
United States
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Conti, Marco; Franciosi, Federica (2018) Acquisition of oocyte competence to develop as an embryo: integrated nuclear and cytoplasmic events. Hum Reprod Update 24:245-266
Han, Seung Jin; Martins, João Pedro Sousa; Yang, Ye et al. (2017) The Translation of Cyclin B1 and B2 is Differentially Regulated during Mouse Oocyte Reentry into the Meiotic Cell Cycle. Sci Rep 7:14077
Yang, Ye; Yang, Cai-Rong; Han, Seung Jin et al. (2017) Maternal mRNAs with distinct 3' UTRs define the temporal pattern of Ccnb1 synthesis during mouse oocyte meiotic maturation. Genes Dev 31:1302-1307