The versatile functions of Sox9 in development, stem cells, and human diseases

Abstract

The transcription factor Sox9 was first discovered in patients with campomelic dysplasia, a haploinsufficiency disorder with skeletal deformities caused by dysregulation of Sox9 expression during chondrogenesis. Since then, its role as a cell fate determiner during embryonic development has been well characterized; Sox9 expression differentiates cells derived from all three germ layers into a large variety of specialized tissues and organs. However, recent data has shown that ectoderm- and endoderm-derived tissues continue to express Sox9 in mature organs and stem cell pools, suggesting its role in cell maintenance and specification during adult life. The versatility of Sox9 may be explained by a combination of post-transcriptional modifications, binding partners, and the tissue type in which it is expressed. Considering its importance during both development and adult life, it follows that dysregulation of Sox9 has been implicated in various congenital and acquired diseases, including fibrosis and cancer. This review provides a summary of the various roles of Sox9 in cell fate specification, stem cell biology, and related human diseases. Ultimately, understanding the mechanisms that regulate Sox9 will be crucial for developing effective therapies to treat disease caused by stem cell dysregulation or even reverse organ damage.

Keywords: Development; Diseases; Sox9; Stem cells; Transcription factor.

Figure 1

Schematic structures of SoxE proteins. In all SoxE proteins, the dimerization domain (DIM) precedes the DNA-binding high mobility group (HMG) domain and two separate transactivation domains are located in a central position (K2) and at the C-terminus (TA). For Sox9, two independent nuclear localization sequences (NLS) and the nuclear export sequences (NES) in the HMG domain, phosphorylation sites (red), and ubiquination/sumolyation sites (blue) are highlighted., . (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Figure 2

Regulation by Sox9-partner complexes. A) Sox9 requires a binding partner to elicit either transcriptional activation or repression., B) Sox9 can function to activate or repress transcription, depending on the partner factor and on the tissue in which it is expressed. During earlier chondrogenesis, Sox9-Gli2/3 complex represses Col10a1 while the “sox trio,” Sox9-Sox5/6 complex, activates Col2a1., C) Sox-partner complexes form a feedforward, self-reinforcing pathway. During male gonad genesis, Sf1 and SRY cooperatively upregulate Sox9 and then, together with Sf1, Sox9 maintains its own expression..

Figure 3

Sox9 expression in pluripotent, fetal, and adult stem and progenitor cells. Sox9 is expressed throughout development, initially in pluripotent founder cells and subsequently in ectodermal, endodermal, and mesodermal derivatives. Sox9 expression is maintained in fetal and adult tissues derived from Sox9+ fetal progenitor cells and also in differentiated cells in some cases., , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

Figure 4

EMT induction by Sox9 in acquired diseases. A) Sox9 is involved in epithelial-mesenchymal transition (EMT) for neural crest delamination during development., , B) Sox9 plays a role in excess extracellular matrix (ECM) deposition and EMT, which may be related to fibrosis. C) Sox9 is important for ECM deposition and EMT,, , , which implies its role in tumor formation and invasive metastasis.