The maternal to zygotic transition is a universal step in animal development, where the embryo transitions from a maternally driven program to a zygotic program. This requires the clearance of the maternally provided mRNAs, and transcription of the zygotic genes. Indeed, these two processes are intimately interconnected, maternal factors drive the activation of the zygotic genes, and zygotic products actively target maternal mRNAs for deadenylation, repression and clearance. This proposal aims to characterize the gene regulatory networks that mediate clearance of the maternal mRNAs and activation of the zygotic genome. By combining high throughput sequencing with experimental manipulation of the early embryo, we will define distinct waves of mRNA decay (aim 1) and zygotic activation (Aim 2). Using computational analysis and experimental validation we will identify the motifs that mediate this regulation at the transcriptional and post-transcriptional level, with the ultimate goal of identifying the factors responsible for this regulation. Together these proposed experiments, will define the gene regulatory network that controls early vertebrate development. The proposed project is relevant for public health at different levels. First, from the stand point of human disease and cancer, pathways that control mRNA stability (including miRNAs) play an important role in aberrant oncogene activation in cancer. By assessing the networks that control mRNA stability and transcriptional activation in the early embryo, this proposal provides novel mechanistic insights into the oncogenic phenotype in cancer. Second, from the stand point of reproductive health, infertility is estimated to affect 15% of reproductive age women and early pregnancy loss corresponds to 25% of all pregnancies with up to 70% in pregnancies after in vitro fertilization. Understanding of the mechanisms of zygotic genome activation and maternal mRNA decay can provide fundamental insights in human infertility and tools to evaluate early loss of fertilized eggs. The results derived from thi project will help us understand how gene expression is regulated in the early embryo during the maternal to zygotic transition to ultimately trigger the activation of the different developmental pathways during gastrulation and axis formation resulting in zygote development.
In all animals, the fertilized egg depends on the instructions provided by the mom to the egg to undergo the first hours of development. Upon fertilization the egg undergo two universally conserved steps. First, it needs to activate the expression of its own instructions (genome), and second, it needs to eliminate the maternal instructions (mRNAs and proteins) to proceed into advanced development. This proposal studies how the vertebrate embryos organize multiple players to undertake these tasks.
|Bazzini, Ariel A; Johnstone, Timothy G; Christiano, Romain et al. (2014) Identification of small ORFs in vertebrates using ribosome footprinting and evolutionary conservation. EMBO J 33:981-93|
|Lee, Miler T; Bonneau, Ashley R; Giraldez, Antonio J (2014) Zygotic genome activation during the maternal-to-zygotic transition. Annu Rev Cell Dev Biol 30:581-613|
|Lee, Miler T; Bonneau, Ashley R; Takacs, Carter M et al. (2013) Nanog, Pou5f1 and SoxB1 activate zygotic gene expression during the maternal-to-zygotic transition. Nature 503:360-4|