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

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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.

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Acknowledgments

Jürgen Behrens and Marina Kreutz are acknowledged for the gift of Ecadherin and Adam19 plasmids, respectively. This work was supported by a grant from the DFG to E.S. (So251/3-1) and from a National Health and Medical Research Council Australia Fellowship to RPH (573705).

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Authors and Affiliations

  1. Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054, Erlangen, Germany

    Mandy H. Paul, Michael Wegner & Elisabeth Sock

  2. Victor Chang Cardiac Research Institute, Darlinghurst and St. Vincent’s Clinical School, University of New South Wales, Kensington, NSW, Australia

    Richard P. Harvey

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  1. Mandy H. Paul
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  2. Richard P. Harvey
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  4. Elisabeth Sock
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Correspondence to Elisabeth Sock.

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Paul, M.H., Harvey, R.P., Wegner, M. et al. Cardiac outflow tract development relies on the complex function of Sox4 and Sox11 in multiple cell types. Cell. Mol. Life Sci. 71, 2931–2945 (2014). https://doi.org/10.1007/s00018-013-1523-x

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  • DOI: https://doi.org/10.1007/s00018-013-1523-x

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