New research presented at the European Society for Paediatric（儿科的） Endocrinology（内分泌学） meeting has found a genetic² region that may control testicle development in the fetus³. Men have XY sex chromosomes⁵, and the development of testes is thought to occur after upregulation of the testicular SOX9 gene¹ pathway, in the presence of factor SRY on the Y chromosome⁴. However, the mechanism⁶ by which this testicular SOX9 upregulation occurs has so far been unclear.

In this study, Dr Jacqueline Hewitt and colleagues from the Royal Children's Hospital Melbourne, Australia, used whole genome mircoarray, and subsequently fluorescence in-situ hybridisation（混合淡化技术） and bioinformatic analyses, to examine the genomes of 30 children with disorders⁷ of sex development (DSD). Nine patients had 46,XX testicular DSD (meaning that although they had XX chromosomes, they had developed as males with testicles), while 21 patients had 46,XY gonadal dysgenesis (meaning that although they had XY chromosomes, they had developed as females, without testicles).

In two of the patients with 46,XX testicular DSD, the researchers found a small region, outside of the SOX9 gene, which was duplicated. Bioinformatic analysis of this duplicated region indicated that it contained an SRY/SOX binding⁹ motif¹⁰, meaning the region may be a regulator of SOX9 gene activity and thus involved in testicle formation. The tandem¹¹（串联） arrangement (i.e. one after another) of the duplications implies they have either a dosage-related or structural¹² effect on the SOX9 gene. The position of these duplications ties in with previous research in patients with a similar condition, familial 46,XX testicular DSD, which also showed that this chromosome region may be involved in testes development.

These findings address key issues in the complex gene regulation system that controls human sex development, in particular the mechanism by which the SOX9 gene is upregulated and testicles are formed in the embryo¹³. This new gene regulatory region appears to be a missing link in the testis development system, and it is significant that duplications in this region can initiate¹⁴ the development of testicles in a person who has XX chromosomes. Further studies are now needed to ascertain¹⁵ if testis development can be initiated¹⁶ by switching on this region in growing cells and in developmental animal models.

Researcher Dr Jacqueline Hewitt, from the Royal Children's Hospital Melbourne, Australia, said:

"We have known for a while that for testes（睾丸） to form in the embryo, a key gene called SOX9 needs to be activated¹⁷. However, until now, the mechanism by which this activation¹⁸ occurs has been unclear.

"Our research indicates that there is a gene regulatory region on chromosome 17, upstream of the SOX9 gene, which is involved in the initiation¹⁹ of testicle development in the fetus. This regulatory region is sited a distance away from the SOX9 gene itself, but functions to switch the gene on, allowing the formation of testicles. This illustrates²⁰ the fundamental importance of not just the actual genes⁸, but also of gene regulation systems in human development. We are only now beginning to understand the mechanisms²¹ of gene regulation, which are essential for the development of a complex organism such as a human child. This research significantly advances our understanding of how the testes develop in the human body."