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ATR-X syndrome and gonadal development
Summary
The ATR-X syndrome, an X-linked recessive developmental disorder affecting males, belongs to a growing list of disorders of sex development (DSD) which affect 1% of all newborns. Clinical features include mental retardation, alpha-thalassemia and skeletal and genital abnormalities. The focus of our work is to investigate the role of ATRX in gonadal development.
Description
To understand the etiology of the testicular phenotype of the ATR-X syndrome, we have developed two mouse models. Similar to ATR-X syndrome patients, ubiquitous inactivation of Atrx in mice results in small testes and an absence of germ cells. Inactivation of Atrx specifically in the testicular Sertoli cells affects Sertoli cell survival, proliferation, and differentiation, resulting in reduced testicular growth.
Future studies aim to investigate these mouse models in detail. To understand how ATRX acts at the molecular level we are attepting to identify testis specific targets. We have established ATRX ChIP, in collaboration with the Institute of Molecular Medicine, on two testicular cell lines.
We are currently undertaking whole genome ChIP Sequencing to identify target genes within these testicular cell-lines. To complement this we will also perform microarray studies on ATRX ‘knockout’ Sertoli cells to identify ATRX-regulated genes.
These studies will improve our understand of the role of ATRX in the testis and provide a clearer understanding of the molecular mechanisms of ATRX failure that lead to DSD and infertility.
Outcomes
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Establish the role of ATRX in gonadal development
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Identify testis-specific targets of ATRX
Funding
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National Health and Medical Research Council
Selected Publications
Bagheri-Fam, S., Argentaro, A., Svingen, T., Combes, A., Sinclair, A., Koopman, P. and Harley, V.R. (2011) Defective survival of proliferating Sertoli cells and androgen receptor function in a mouse model of the ATR-X syndrome. Human Molecular Genetics 20: 2213-2224
Tang, P., Argentaro, A., Pask, A.J., O’Donnell, L., Marshall-Graves, J., Familari, M. and Harley, V.R. (2011) Localisation of the chromatin remodelling protein, ATRX in the adult testis. Journal of Reproduction & Development 57: 317-321