Melbourne, VIC, Australia. Researchers have located a gene regulatory region which appears to control testis development in the foetus without regard to chromosomal organization.

The research raises questions about the complex gene regulation system that controls human sex development, especially the mechanism by which the SOX9 gene is upregulated and testicles form in the embryo, even in the presence of an XX chromosome.


Males have XY sex chromosomes, and the development of testes is thought to occur after upregulation of the testicular SOX9 gene pathway, in the presence of factor SRY on the Y chromosome. The mechanism by which this testicular SOX9 upregulation occurs has so far been unclear. However, the examination of genomic information from children with disorders of sex development (DSD) offer a pathway to understand how testicles can form without regard to whether an individual is XX or XY.

The project team used whole genome mircoarray, and subsequently fluorescence in-situ hybridisation and bioinformatic analyses, to examine the genomes of 30 children with DSDs.

• Nine patients had 46,XX testicular DSD (meaning that although they had XX chromosomes, they had developed as males with testicles)
  
  
• 21 patients had 46,XY gonadal dysgenesis. 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 binding motif, meaning the region may be a regulator of SOX9 gene activity and thus involved in testicle formation.

The tandem arrangement (i.e., one after another) of the duplications implies they have either a dosage-related or structural effect on the SOX9 gene. Duplications in this region can initiate the development of testicles in a person who has XX chromosomes.

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.

Dr Jacqueline Hewitt and colleagues are from the Royal Children's Hospital (RCH) in Melbourne, Australia.

They presented initial project findings during their presentation at the annual meeting of the European Society for Paediatric Endocrinology (ESPE).It has been known for awhile that testes formation in the embryo depends on activation of the key SOX9 gene, but definitive description of the mechanism by which it occurs (or departs from developmental norms) has been elusive.

Jacqueline Hewitt says "Our research indicates that there is a gene regulatory region on chromosome 17, upstream of the SOX9 gene, which is involved in the initiation of testicle development in the foetus." 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 illustrates the fundamental importance of not just the actual genes," Hewitt says, "but also of gene regulation systems in human development. We are only now beginning to understand the mechanisms 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."

Further studies are now needed to ascertain if testis development can be initiated by switching on this region in growing cells and in developmental animal models.

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