MicroRNA-34a is dispensable for p53 function as teratogenesis inducer

Eyal Mor, Lin He, Arkady Torchinsky*, Noam Shomron

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish
Pages (from-to)1749-1763
Number of pages15
JournalArchives of Toxicology
Volume88
Issue number9
DOIs
StatePublished - Sep 2014

Funding

FundersFunder number
Amedee Maratier Institute for the Study of Blindness
Wolfson Family Charitable Fund
National Cancer InstituteR01CA139067
Israel Science Foundation41/11

    Keywords

    • Development
    • Limbs
    • Teratogens
    • miR-34
    • miRNA
    • microRNA
    • p53

    Fingerprint

    Dive into the research topics of 'MicroRNA-34a is dispensable for p53 function as teratogenesis inducer'. Together they form a unique fingerprint.

    Cite this