microRNAs (miRNAs) encode ~22nt small RNAs that regulate deadenylation, translation, and decay of their target mRNAs. With the potential to regulate more that 30% of the human genes, miRNAs play fundamental roles in every aspect of biology from human development, to human disease including neuropsychiatric disorders and cancer. The long-term goal of our research is to understand how miRNAs regulate gene expression to orchestrate early embryogenesis, using zebrafish as a model system. In particular, this proposal focuses on how microRNAs regulate potent signaling molecules to control cell migration in two different contexts during development: lateral line migration and angiogenesis using zebrafish as a model system. Our preliminary studies have used single microRNA knock down and mutants in the microRNA processing pathway indicate that disrupting miR-1 and miR-430 function causes i) abnormal migration of the lateral line primordium (a model for placode migration in vertebrates) and ii) increased migration during angiogenesis (in the intersegmental vessels, ISV). This proposal combines embryological manipulations and live imaging, to understand how miR-1 regulate endothelial cell migration during angiogenesis Aim 1 and understand how miR-430 ensures that different migratory paths driven by the chemokine signaling sdf1a remain separated during development to avoid mis-targeted migration Aim 2. In summary, the proposed experiments have the long term goal of understanding i) how miRNAs regulate individual miRNA targets to orchestrate embryonic development during cell migration, and angiogenesis, ii) how they modulate the expression of potent signaling molecules to ensure the appropriate level of signaling between tissues.
microRNA are small non-coding RNAs that have important regulatory roles in the genome with far reaching roles from human development to cancer. This proposal studies how these microRNAs control the expression of potent migration cues to regulate migration of different cells types in the developing vertebrate embryo to ensure accurate targeting and avoid mis migration.
|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|
|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; Takacs, Carter M et al. (2013) Nanog, Pou5f1 and SoxB1 activate zygotic gene expression during the maternal-to-zygotic transition. Nature 503:360-4|
|Bazzini, Ariel A; Lee, Miler T; Giraldez, Antonio J (2012) Ribosome profiling shows that miR-430 reduces translation before causing mRNA decay in zebrafish. Science 336:233-7|
|Staton, Alison A; Giraldez, Antonio J (2011) Use of target protector morpholinos to analyze the physiological roles of specific miRNA-mRNA pairs in vivo. Nat Protoc 6:2035-49|
|Staton, Alison A; Knaut, Holger; Giraldez, Antonio J (2011) miRNA regulation of Sdf1 chemokine signaling provides genetic robustness to germ cell migration. Nat Genet 43:204-11|
|Bazzini, Ariel A; Giraldez, Antonio J (2011) MicroRNAs sculpt gene expression in embryonic development: new insights from plants. Dev Cell 20:3-4|
|Sander, Jeffry D; Dahlborg, Elizabeth J; Goodwin, Mathew J et al. (2011) Selection-free zinc-finger-nuclease engineering by context-dependent assembly (CoDA). Nat Methods 8:67-9|
|Zhu, Cong; Smith, Tom; McNulty, Joseph et al. (2011) Evaluation and application of modularly assembled zinc-finger nucleases in zebrafish. Development 138:4555-64|
|Cifuentes, Daniel; Xue, Huiling; Taylor, David W et al. (2010) A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity. Science 328:1694-8|
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