ABSTRACT
The right ventricle and outflow tract of the developing heart are derived from mesodermal progenitor cells from the second heart field (SHF). SHF cells have been characterized by expression of the transcription factor Islet-1 (Isl1). Although Isl1 expression has also been reported in the venous pole, the specific contribution of the SHF to this part of the heart is unknown. Here we show that Isl1 is strongly expressed in the dorsal mesenchymal protrusion (DMP), a non-endocardially-derived mesenchymal structure involved in atrioventricular septation. We further demonstrate that abnormal development of the SHF-derived DMP is associated with the pathogenesis of atrioventricular septal defects. These results identify a novel role for the SHF.
Subject(s)
Gene Expression Regulation, Developmental , Heart Defects, Congenital/physiopathology , Heart/embryology , Heart/physiology , Homeodomain Proteins/genetics , Animals , Female , Gestational Age , Heart Defects, Congenital/genetics , Homeobox Protein Nkx-2.5 , Homeodomain Proteins/metabolism , LIM-Homeodomain Proteins , Mesoderm/embryology , Mesoderm/physiology , Mice , Mice, Mutant Strains , Pregnancy , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
To expand our insight into cardiac development, a comparative DNA microarray analysis was performed using tissues from the atrioventricular junction (AVJ) and ventricular chambers of mouse hearts at embryonic day (ED) 10.5-11.0. This comparison revealed differential expression of approximately 200 genes, including cartilage link protein 1 (Crtl1). Crtl1 stabilizes the interaction between hyaluronan (HA) and versican, two extracellular matrix components essential for cardiac development. Immunohistochemical studies showed that, initially, Crtl1, versican, and HA are co-expressed in the endocardial lining of the heart, and in the endocardially derived mesenchyme of the AVJ and outflow tract (OFT). At later stages, this co-expression becomes restricted to discrete populations of endocardially derived mesenchyme. Histological analysis of the Crtl1-deficient mouse revealed a spectrum of cardiac malformations, including AV septal and myocardial defects, while expression studies showed a significant reduction in versican levels. Subsequent analysis of the hdf mouse, which carries an insertional mutation in the versican gene (CSPG2), demonstrated that haploinsufficient versican mice display septal defects resembling those seen in Crtl1(-/-) embryos, suggesting that reduced versican expression may contribute to a subset of the cardiac abnormalities observed in the Crtl1(-/-) mouse. Combined, these findings establish an important role for Crtl1 in heart development.
