Regulation of zebrafish heart regeneration by miR-133

Abstract

Zebrafish regenerate cardiac muscle after severe injuries through the activation and proliferation of spared cardiomyocytes. Little is known about factors that control these events. Here we investigated the extent to which miRNAs regulate zebrafish heart regeneration. Microarray analysis identified many miRNAs with increased or reduced levels during regeneration. miR-133, a miRNA with known roles in cardiac development and disease, showed diminished expression during regeneration. Induced transgenic elevation of miR-133 levels after injury inhibited myocardial regeneration, while transgenic miR-133 depletion enhanced cardiomyocyte proliferation. Expression analyses indicated that cell cycle factors mps1, cdc37, and PA2G4, and cell junction components cx43 and cldn5, are miR-133 targets during regeneration. With pharmacological inhibition and EGFP sensor interaction studies, we demonstrated that cx43 is a new miR-133 target and regeneration gene. Our results reveal dynamic regulation of miRNAs during heart regeneration, and indicate that miR-133 restricts injury-induced cardiomyocyte proliferation.

Identification and characterization of tumor suppressor and oncogenic miRNAs in gastric cancer

“…Originally, a number of studies determined that miR-133 is critical in regulating heart and skeletal muscle development (18,19). However, a more recent study demonstrated that miR-133 is aberrantly expressed in tumors, and that miR-133a/b can inhibit the proliferation, and metastasis of bladder and prostate cancer by regulating the expression of the epidermal growth factor receptor (20,21).…”

MicroRNA in cardiovascular biology and disease

“…Upregulation of miR-133 diminishes its regenerative potential, whereas decreasing the level of miR-133 with specific miRNA sponges promotes regeneration. 24 To sum up, the miR-15 and miR-133 families attenuate the regenerative capacity of the heart by inhibiting cardiomyocyte proliferation.…”

The admiR-able advances in cardiovascular biology through the zebrafish model system

“…In summary, miRNA-133, a conserved miRNA known to have a role in cardiac development and disease in mammals [12], regulates zebrafish heart regeneration [79]. This work further demonstrates the versatility of the zebrafish model for miRNA studies not only during embryonic development, but also in the adult animal.…”

“…Placing a miRNA sponge in the 3 0 -UTR of a reporter gene (dGFP in most cases), it is also possible to obtain information about the miRNA expression pattern and to down-modulate it at the same time. Interestingly, miRNA sponges have also been used to generate miRNA tissue-specific and stable knockdown [78,79]. The use of sponges can be useful to overcome morpholinos off-target effects and to obtain a stable or prolonged knockdown not achievable with morpholinos because of their relative short half-life.…”

“…These findings have suggested a potential role of microRNA in the regulation of heart regeneration and offer hope that this event could also be induced in mammals. Yin et al [79], through a microarray analysis of microRNA differentially expressed after the resection of the ventricle apex of the adult zebrafish heart, found that miRNA-133 expression correlates with the regeneration process. In zebrafish, miRNA-133 is downregulated after apex amputation, but progressively returns to be expressed to baseline when regeneration is completed.…”