Sox9 Expression in the Second Heart Field; A Morphological Assessment of the Importance to Cardiac Development with Emphasis on Atrioventricular Septation

Abstract

Failure to form the septal structures that separate the left and right cardiac chambers results in defects that allow shunting of blood from one side of the heart to the other, leading to the mixing of oxygenated and de-oxygenated blood. The atrioventricular (AV) mesenchymal complex, consisting of the AV cushions, the Dorsal Mesenchymal Protrusion (DMP), and the mesenchymal cap, plays a crucial role in AV septation. Cells found in these structures derive from different cell lineages. In this study we have investigated the role of the transcription factor Sox9 in the Second Heart Field (SHF) with the emphasis on the formation of the atrioventricular septal complex. Using a mouse model in which Sox9 is conditionally deleted from the SHF we demonstrate that in this model virtually all mouse embryos develop septal abnormalities, including complete atrioventricular septal defects (cAVSDs) and isolated ventricular septal defects. Our morphological analyses indicate that perturbation of the development of the mesenchymal cap appears to play a crucial role in the pathogenesis of the atrial septal defects observed in the AVSDs and suggests that this component of the AV mesenchymal complex might play a more important role in AV septation than previously appreciated.

Mutations in genes related to myocyte contraction and ventricular septum development in non-syndromic tetralogy of Fallot

“…Of final note, there was also significant enrichment of target genes of four different transcription factors, all of which have previously been tied to cardiac development or injury response. The most significant is SOX9 (7.6-fold enrichment, p = 3.98 × 10 −5 , B-H p = 0.04), which coincidentally is the only transcription factor that has been previously reported in relation to TOF and is critical for ventricular septum formation (81,82). NKX6.2 (7.3-fold enrichment, p = 5.01 × 10 −5 , B-H p = 0.05) has been previously tied to CHD.…”

“…Our human data in the current study supports this hypothesis as indicated by significant overlap of pathways associated with cell proliferation and with genes necessary for normal ventricle, outflow tract and myocyte development that are expressed in the first and second heart field, such as EDNRA and FAT4, and migratory cardiac neural crest cells, such as MED13l . In this regard, the enrichment for target genes of SOX9 is particularly intriguing, as loss of SOX9 has been demonstrated to result in TOF in murine models via a loss of second heart field contribution to outflow tract mesenchyme resulting in a perturbation of the proximal outflow tract septum and an associated membranous ventricular septal defect ( 81 ). This loss of SOX9 was also associated with cleft palate in addition to skeletal malformations and sex reversal.…”