Notably, miR-21 exerts its actions by regulating Gefitinib the
expression of the same target genes as mouse/human miR-21, namely Sprouty, Pdcd4, and Ptenb. 58 MiR-138, which was specifically expressed in the developing ventricular chamber, was shown to be required for establishment of chamber-specific gene expression patterns. MiR-138 acts by targeting multiple members of the retinoic acid signaling pathway, to prevent ventricular expansion of gene expression normally restricted to the atrio-ventricular valve region. 59 Last, but not least, a recent study reported a putative mutual cross-regulation mechanism between the TF Tbx5 and miR-218-1, and demonstrated its implication in heart development in zebrafish. 60 Of note, Tbx5 gene expression levels have an overt effect on heart development, and their dysregulation has been related with the establishment of congenital heart defects. Similarly, the Tbx5 downstream targets miR-218-1 and its host gene Slit2 are
known to be involved in heart development. Specifically, miR-218-1 was shown to suppress the expression of Robo receptors (Robo1,2), which interact with Slit family ligands to facilitate cell guidance during development. Evidently, the miR-218-1 and Slit/Robo form a regulatory loop required for heart tube formation in zebrafish. 61 The exact role of miR-218-1 in Tbx-5 regulation, though, is still being explored. 60 Additional information on cardiac development-related miRNAs has emerged from studies in the Mexican axolotl (salamander). Interestingly, a group investigated the role of a human fetal heart microRNA which is thought to be related to the human miR-499 family, and was therefore named miR-499c, in mutant axolotl hearts in organ culture. Accordingly, the axolotl hearts with abnormal development (without tropomyosin expression, sporadically beating etc) were incubated with the miR-499c, which was able to induce expression of cardiac markers (tropomyosin, troponin, α-syntrophin) in these hearts. 62 Evidently, miR-499c treatment promoted the formation AV-951 of cardiac myofibrils in mutant
axolotl hearts, thus showing the potential to restore normal embryonic heart development in this species. 62 As presented in the following section, miR-499 possibly plays a key role during human cardiomyocyte (CMC) differentiation, and hence the role of the new miR-499c in cardiac development requires further investigation. miRNA expression in embryonic stem cell-derived cardiomyocytes However informative studies in animal models may be, they still have to be validated in humans. To this end, human embryonic stem cell-derived cardiomyocytes (hESC-derived CMCs) are now providing valuable new insights. The first miRNA profiling study of hESC-derived CMCs led to the identification of 711 unique miRNAs.