Abstract 1114: Deregulation of MicroRNAs in the Heart of c-kit-Defective Mice
MicroRNAs (miRNAs) are a family of non-coding RNAs that regulate gene expression by repressing mRNA function at the post-transcriptional level. Recently, the involvement of miRNAs in the modulation of cardiac function has been described in vivo in the developing and adult heart. Whether miRNAs play an important role in the control of the growth and differentiation of c-kit-positive cardiac progenitor cells (CPCs) is currently unknown. Therefore, two transgenic mouse models characterized by defects in the c-kit receptor or its ligand, stem cell factor (SCF), were studied in combination with wild-type littermates. The first one has a spontaneous point mutation of the c-kit receptor in one allele (WV) coupled with an amino acid deletion in the other allele (W); and the second has a complete deletion of the SCF gene locus in one allele (Sl) and deletion of the membrane-bound ligand in the other (Sld). The ventricular myocardium of transgenic and non-transgenic mice was analyzed with respect to miRNA expression by microarray. We have identified three miRNAs that showed an extremely high level of expression in the heart of transgenic and non-transgenic animals: miR-150, miR-451 and miR-805. These miRNAs have not been described previously in the myocardium and were consistently upregulated in the heart of wild-type mice; a 1.4 –1.8-fold difference was found with respect to transgenic animals. The major difference was detected for miR-150. So far, this miRNA was considered to be restricted to hematopoietic progenitors. Surveying the predicted targets of miR-150, we identified a cluster of genes involved in cell proliferation that were expected to be upregulated in W/WV and Sl/Sld mice: Akt3, ELK1, FOXP1, Pim-1, IGF-1, Myb and PA2G4. Consistently, W/WV mice showed a two-fold or larger mRNA and protein levels for genes implicated in cell cycle progression. A similar analysis was not possible for miR-451 and miR-805 since the predicted targets of these miRNAs remain to be recognized. In conclusion, a novel miRNA critical for hematopoiesis has been identified in the heart and this miRNA is downregulated when defects of c-kit signaling are present.