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The DGCR8 gene, encoding a critical miRNA processing protein, maps within the hemizygous region in patients with 22q11.2 deletion syndrome. Most patients have malformations of the cardiac outflow tract that is derived in part from the anterior second heart field (aSHF) mesoderm. To understand the function of Dgcr8 in the aSHF, we inactivated it in mice using Mef2c-AHF-Cre. Inactivation resulted in a fully penetrant persistent truncus arteriosus and a hypoplastic right ventricle leading to lethality by E14.5. To understand the molecular mechanism for this phenotype, we performed gene expression profiling of the aSHF and the cardiac outflow tract with right ventricle in conditional null versus normal mouse littermates at stage E9.5 prior to morphology changes. We identified dysregulation of mRNA gene expression, of which some are relevant to cardiogenesis. Many pri-miRNA genes were strongly increased in expression in mutant embryos along with reduced expression of mature miRNA genes. We further examined the individual, mature miRNAs that were decreased in expression along with pri-miRNAs that were accumulated that could be direct effects due to loss of Dgcr8. Among these genes, were miR-1a, miR-133a, miR-134, miR143 and miR145a, which have known functions in heart development. These early mRNA and miRNA changes may in part, explain the first steps that lead to the resulting phenotype in Dgcr8 aSHF conditional mutant embryos. [Display omitted] • The DGCR8 gene encodes a miRNA processing protein. • DGCR8 is in the chromosome 22q11.2 region deleted in patients with 22q11.2DS. • Inactivation in the anterior second heart field results in severe heart defects. • Inactivation of Dgcr8 in mice causes dysregulation of cardiac gene expression. • miRNAs important for cardiac development are decreased in expression. The DGCR8 gene encodes a subunit of a protein complex that processes miRNAs and it is in the hemizygously deleted region on chromosome 22 in patients with 22q11.2 deletion syndrome (22q11.2DS). To understand the specific functions of Dgcr8 in mouse heart development, we inactivated it in the anterior second heart field. We found severe heart malformations, dysregulation of mRNA expression, increased expression of pri-miRNAs with decreased expression of mature miRNAs related to heart development. This work contributes to our understanding of DGCR8 functions in heart development in mammals. [ABSTRACT FROM AUTHOR]