Cardiac outflow tract development relies on the complex function of Sox4 and Sox11 in multiple cell types

Abstract

Congenital heart defects represent the most common human birth defects and are often life-threatening. Frequently, they are caused by abnormalities of the outflow tract whose formation results from coordinated development of cells from mesodermal and neural crest origin and depends on the activity of many different transcription factors. However, place, time, and mode of action have only been analyzed for a few of them. Here we assess the contribution of the closely related high-mobility-group transcription factors Sox4 and Sox11 to outflow tract development and determine their function. Using cell-type-specific deletion in the mouse, we show that Sox11 is required for proper development in both mesodermal cells and neural crest cells. Deletion in either mesoderm or neural crest, or both, leads to outflow tract defects ranging from double outlet right ventricle to common arterial trunk. Sox4 supports Sox11 in its function, but has additional roles with relevance for outflow tract formation in other cell types. The two Sox proteins are dispensable during early phases of cardiac neural crest development including neural tube emigration, proliferation, and migration through the pharyngeal arches. They become essential after arrival of the neural crest cells in the outflow tract for their proper differentiation and interaction with each other as well as with the environment through regulation of cytoskeletal, cell adhesion, and extracellular matrix molecules. Our results demonstrate that Sox4 and Sox11 have multiple functions in several cell types during outflow tract formation and may thus help to understand the basis of congenital heart defects in humans.

MicroRNAs: pleiotropic players in congenital heart disease and regeneration

“…The results showed that miR-421 overexpression in normal cardiomyocytes led to a downregulation of SOX4 (SRF-Box 4), whereas miR-421 knockdown in primary cells that were derived from TOF patients led to an up-regulation of SOX4. This supports the hypothesis of an inverse correlation of miR-421 and SOX4, which is known as a central regulator of Notch and Wnt signaling and also has been implicated to play a role in the development of cardiac outflow tract (28,65). However, miR-421 has multiple sets of downstream targets, and the potential direct correlation between this regulated miR and the altered expression of SOX4 and its resulting impact on the Notch and Wnt pathway remains to be evaluated (27).…”

Sox4 regulates choroid fissure closure by limiting Hedgehog signaling during ocular morphogenesis

“…SoxC family members display overlapping expression domains in several embryonic tissues, including neuronal and mesenchymal progenitor cells (Dy et al, 2008). The SoxC factors function redundantly in the development of some tissues, such as the nervous system, but also have distinct roles in the development of other tissues, such as the heart (Bergsland et al, 2006; Bhattaram et al, 2010; Penzo-Mendez, 2010; Paul et al, 2013). Moreover, Sox11 null mice survive several days longer than Sox4 null mice, suggesting non-redundant roles for these two proteins in early embryogenesis.…”

Inflammatory Cytokines Stabilize SOXC Transcription Factors to Mediate the Transformation of Fibroblast‐Like Synoviocytes in Arthritic Disease

“…Our observation that SOXC genes may be dispensable for joint integrity in juvenile and young adult mice was not predicted. Indeed, we were able to detect the proteins and their mRNA in the synovium and articular cartilage of adult mice, and we and others previously showed the indispensability of SOXC genes for joint formation in mouse embryos (11,(13)(14)(15)(28)(29)(30). A possible explanation is that the SOXC proteins are present at very low levels or in an inactive form in healthy (nonarthritic) adult synovium and therefore cannot exert significant functions.…”