The egg-to-embryo transition entails transforming a highly differentiated oocyte into totipotent blastomeres, and represents one of the earliest obstacles that must be successfully hurdled for continued development. Degradation of maternal mRNAs (which initiates during oocyte maturation) and reprogramming gene expression (which is clearly evident in 2-cell embryos) lie at the heart of this transition. The overarching objective of the proposed studies is to use mouse as a model system to gain deeper insights into the molecular basis for each of these underlying events, i.e., degradation of maternal mRNA and reprogramming gene expression. An apparently universal feature of the egg-to-embryo transition is degradation of maternal mRNAs either during maturation or shortly after fertilization/genome activation. How mRNAs are degraded is gaining increased attention because mRNA degradation is highly regulated. Moreover, there is growing consensus that degradation of maternal mRNA is essential for the egg-to-embryo transition.
Specific Aim 1 will test the hypothesis that recruitment of maternal mRNAs encoding DCP1A &2 results in the 5'mRNA degradation pathway as the dominant pathway. The proposed studies will also define the role of the maturation-associated phosphorylation of DCP2 in mRNA degradation. Results of these studies will provide a detailed understanding of degradation of maternal mRNAs during the course of oocyte maturation. How reprogramming of gene expression occurs and uses a maternally inherited transcription apparatus remains enigmatic.
Specific Aim 2 will test the hypothesis that recruitment during oocyte maturation of mRNAs encoding chromatin remodelers and transcription factors is essential for reprogramming gene expression. Results of these studies will likely provide a simple and elegant solution to this problem. Post-transcriptional mechanisms are rapidly gaining attention as a major locus of regulation of gene expression, and in particular, the role of microRNAs (miRNA) in mRNA degradation. Although oocytes express a plethora of miRNAs, as well as mediators of their function, miRNA activity that leads to mRNA degradation functions poorly in oocytes and inhibiting miRNA biogenesis has no marked effect on oocyte and preimplantation development.
Specific Aim 3 will identify the molecular basis for failure of miRNAs to promote degradation of their target mRNAs in oocytes. Understanding the basis for this failure will shed further light on the role of small RNAs in oocyte development. Taken together, results of the proposed studies will generate a detailed understanding of two critical processes that underly the egg-to- embryo transition, i.e., maternal mRNA degradation and reprogramming gene expression.
The proposed studies will provide new information regarding molecular mechanisms underlying the egg-to- embryo transition. The results of these studies will provide further insights into how eggs develop into early embryos, and thereby impact the treatment of human infertility and assisted reproduction technologies.
|Abe, Ken-Ichiro; Funaya, Satoshi; Tsukioka, Dai et al. (2018) Minor zygotic gene activation is essential for mouse preimplantation development. Proc Natl Acad Sci U S A 115:E6780-E6788|
|Horvat, Filip; Fulka, Helena; Jankele, Radek et al. (2018) Role of Cnot6l in maternal mRNA turnover. Life Sci Alliance 1:e201800084|
|Franke, Vedran; Ganesh, Sravya; Karlic, Rosa et al. (2017) Long terminal repeats power evolution of genes and gene expression programs in mammalian oocytes and zygotes. Genome Res 27:1384-1394|
|Mayer, Alexandra; Baran, Vladimir; Sakakibara, Yogo et al. (2016) DNA damage response during mouse oocyte maturation. Cell Cycle 15:546-58|
|Ma, P; Schultz, R M (2016) HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation. Cell Death Differ 23:1119-27|
|Svoboda, Petr; Franke, Vedran; Schultz, Richard M (2015) Sculpting the Transcriptome During the Oocyte-to-Embryo Transition in Mouse. Curr Top Dev Biol 113:305-49|
|Balboula, Ahmed Z; Stein, Paula; Schultz, Richard M et al. (2015) RBBP4 regulates histone deacetylation and bipolar spindle assembly during oocyte maturation in the mouse. Biol Reprod 92:105|
|Jimenez, Richard; Melo, Eduardo O; Davydenko, Olga et al. (2015) Maternal SIN3A regulates reprogramming of gene expression during mouse preimplantation development. Biol Reprod 93:89|
|Abe, Ken-Ichiro; Yamamoto, Ryoma; Franke, Vedran et al. (2015) The first murine zygotic transcription is promiscuous and uncoupled from splicing and 3' processing. EMBO J 34:1523-37|
|Stein, Paula; Rozhkov, Nikolay V; Li, Fan et al. (2015) Essential Role for endogenous siRNAs during meiosis in mouse oocytes. PLoS Genet 11:e1005013|
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