Abstract 16797: Mechanisms That Repress BMP2 in Mesenchymal Cells
BMP2 is an essential protein. A short burst of BMP2 promotes repair after vascular injury. However, excessive BMP2 levels in the vasculature and heart valves promote pathological calcification. A sequence within the 3’UTR of the mRNA termed the “ultra-conserved sequence” (UCS) has been largely unchanged since fishes and mammals diverged. Cre-lox mediated deletion of the UCS in a mouse reporter transgene revealed that one role of the UCS is to repress BMP2 synthesis in heart valves and vascular cells. We are now testing the hypothesis that normal heart morphology requires UCS-mediated restraint of BMP2 synthesis. We used homologous recombination to generate a Bmp2 allele with the endogenous Bmp2 UCS flanked by loxP sites. We bred this strain to strains that express Cre-recombinase thus deleting the UCS. The survival of pups with homozygous loss of the UCS was significantly reduced. We are now assessing embryonic heart morphology in these strains. We also postulate that the regulatory proteins and microRNAs that mediate UCS-mediated repression may be exploited to pharmacologically reawaken BMP2 repression in tissues undergoing pathological pathologies. Specific miRNAs inhibit UCS-bearing reporters and mutations of miRNA binding sites activate these reporters. Interestingly, an A+U rich element (ARE) known to bind HuR (generally an activator) and AUF1 (a repressor) is embedded in a conserved miRNA binding site. Selective mutations of the ARE and the miRNA seed indicate that repressive molecules bind this site in mesenchymal cells where the UCS functions as a repressor.
Author Disclosures: M. Rogers: None. A. Fotinos: None. T. Shah: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.