title: MicroRNA-34a is dispensable for p53 function as teratogenesis inducer.
abstract: The tumor suppressor protein p53 is a powerful regulator of the embryo's susceptibility to diverse teratogenic stimuli, functioning both as a teratogenesis inducer and suppressor. However, the targets that p53 engages to fulfill its functions remain largely undefined. We asked whether the microRNA (miRNA) miR-34 family, identified as one of the main targets of p53, mediates its function as a teratogenesis inducer. For this, pregnant ICR-, p53- and miR-34a-deficient mice, as well as rats, were exposed to 5-aza-2'-deoxycytidine (5-aza), a teratogen inducing limb reduction anomalies (LRA) of the hindlimbs in mice and either the hindlimbs or forelimbs in rats. Using hind- and forelimb buds of 5-aza-exposed embryos, we identified that the miR-34 family members are the most upregulated miRNAs in mouse and rat limb buds, with their increase level being significantly higher in limb buds destined for LRA. We showed that p53 mediates the 5-aza-induced miR-34 transcription followed by met proto-oncogene and growth-arrest-specific 1 target suppression in embryonic limb buds. We demonstrated that p53 regulates the teratogenic response to 5-aza acting as a teratogenesis inducer albeit miR-34a deletion does not affect the susceptibility of mice to 5-aza. Overall, our study thoroughly characterizes the expression and regulation of miR-34 family in teratogen-resistant and teratogen-sensitive embryonic structures and discusses the involvement of epigenetic miRNA-mediated pathway(s) in induced teratogenesis.
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, 69978, Tel Aviv, Israel, eyalmoro@gmail.com.
authors.forename: Eyal
authors.initials: E
authors.lastname: Mor
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.forename: Arkady
authors.initials: A
authors.lastname: Torchinsky
authors.forename: Noam
authors.initials: N
authors.lastname: Shomron
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000378:metabolism*; D000818:Animals; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006579:Heterozygote; D018878:Limb Buds / Q000002:abnormalities / Q000187:drug effects* / Q000378:metabolism; D017880:Limb Deformities, Congenital / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D011247:Pregnancy; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C560944:MIRN34 microRNA, rat; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D013723:Teratogens; D016159:Tumor Suppressor Protein p53; D000077209:Decitabine; D001374:Azacitidine