MicroRNA-34 and p53 unlocking Mystery of Thalidomide’s Malformation of Limbs

TAU research pinpoints mechanism causing rare and severe congenital syndrome

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Science Daily news unlocking mystery of thalidomide’s malformation of limbs

Shortly after thalidomide was released to market in the 1950s, a reported 10,000 infants were born with an extreme form of a rare congenital syndrome – phocomelia – which caused death in 50 percent of cases.

Researchers from Tel Aviv University’s Sackler Faculty of Medicine have identified a regulator – microRNA (miRNA) miR-34 family – responsible for the malformation of limbs in phocomelia, pinpointing a specific target for possible future intervention.

The study reflects the role that epigenetic regulation plays in the development of disease. Embryonic development can be caused by a genetic mutation or by turning the genes on or off without any change in the genetic code itself.

2014 Study 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.

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