miRNA-processing enzyme Dicer is necessary for cardiac outflow tract alignment and chamber septation.
MicroRNAs (miRNAs) have previously been implicated in a number of developmental processes, including development of the ventricular myocardium of the heart. To determine what, if any, additional roles miRNAs play in cardiogenesis, we deleted the miRNA-processing enzyme Dicer specifically in the developing murine heart. Embryos lacking cardiac Dicer lived longer than reported in previous studies using different alleles to remove cardiac Dicer activity and displayed a highly penetrant phenotype of double outlet right ventricle with a concurrent ventricular septal defect. Before the defect's onset, Pitx2c and Sema3c, both required for outflow tract morphogenesis, were up-regulated in Dicer-deficient hearts. Interestingly, mesenchymal apoptosis in the outflow tract normally required for outflow tract alignment was greatly decreased in the mutants, likely contributing directly to the observed phenotype. In sum, we demonstrate here a specific developmental process, that of outflow tract morphogenesis, being hindered by the deletion of miRNAs during cardiogenesis.
Saxena
Ankur
A
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Tabin
Clifford J
CJ
D000818:Animals; D001011:Aorta / Q000033:anatomy & histology / Q000196:embryology; D016923:Cell Death / Q000502:physiology; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D017353:Gene Deletion; D006321:Heart / Q000033:anatomy & histology / Q000196:embryology; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009024:Morphogenesis / Q000502:physiology*; D009206:Myocardium / Q000201:enzymology*; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000097577:Homeobox Protein PITX2
D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D035683:MicroRNAs; D043244:Ribonuclease III; D039961:Semaphorins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C484469:Nkx2-5 protein, mouse; C510203:semaphorin 3C protein, mouse