PDF(Pubmed)
Abstract：
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.
摘要：
DGCR8基因,编码关键miRNA加工蛋白，22q11.2缺失综合征患者的半合子区域内的地图。大多数患者的心脏流出道畸形部分源自前第二心脏区域（aSHF）中胚层。要了解Dgcr8在aSHF中的功能，我们使用Mef2c-AHF-Cre在小鼠体内灭活它。失活导致完全渗透的持续性动脉干和右心室发育不良，导致E14.5致死。为了了解这种表型的分子机制，在形态学改变前的E9.5阶段,我们对条件无效小鼠和正常同窝小鼠的右心室aSHF和心脏流出道进行了基因表达谱分析.我们发现mRNA基因表达失调，其中一些与心脏发生有关。许多pri-miRNA基因在突变胚胎中的表达强烈增加,同时成熟miRNA基因的表达降低。我们进一步检查了个人，表达降低的成熟miRNA以及积累的pri-miRNA,其可能由于Dgcr8的损失而直接作用。在这些基因中,是miR-1a，miR-133a,miR-134,miR143和miR145a,在心脏发育中具有已知功能。这些早期mRNA和miRNA的变化可能在某种程度上，解释导致Dgcr8aSHF条件突变胚胎表型的第一步。
