The regulation of Sox9 expression in the gonad

Abstract

The bipotential nature of cell types in the early developing gonad and the process of sex determination leading to either testis or ovary differentiation makes this an interesting system in which to study transcriptional regulation of gene expression and cell fate decisions. SOX9 is a transcription factor with multiple roles during development, including being a key player in mediating testis differentiation and therefore subsequent male development. Loss of Sox9 expression in both humans and mice results in XY female development, whereas its inappropriate activation in XX embryonic gonads can give male development. Multiple cases of Disorders of Sex Development in human patients or sex reversal in mice and other vertebrates can be explained by mutations affecting upstream regulators of Sox9 expression, such as the product of the Y chromosome gene Sry that triggers testis differentiation. Other cases are due to mutations in the Sox9 gene itself, including its own regulatory region. Indeed, rearrangements in and around the Sox9 genomic locus indicate the presence of multiple critical enhancers and the complex nature of its regulation. Here we summarize what is known about the role of Sox9 and its regulation during gonad development, including recently discovered critical enhancers. We also discuss higher order chromatin organization and how this might be involved. We end with some interesting future directions that have the potential to further enrich our understanding on the complex, multi-layered regulation controlling Sox9 expression in the gonads.

Keywords: 3D genome architecture; Disorders of sex development; Enhancers; Regulatory elements; Sex determination; Sex reversal; Sox9; Testis development; Transcription factor.