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| Human Molecular : Genetics |
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Research Projects available: 1. The role of SRY in the brain Supervisors: Dr Joohyung Lee and Associate Professor Vincent Harley Parkinson’s Disease (PD) causes involuntary movement or tremors. Interestingly, PD occurs 1.5 times more often in men than in women. We think this could be due in part to the sex chromosome differences between males (XY) and females (XX). We have evidence that SRY, the “male only” gene on the Y chromosome responsible for the presence of testicles, also makes SRY protein in men’s brains. When SRY is removed from rats’ brains, the male rats develop movement problems reminiscent of those seen in PD which are reversed when SRY levels are restored. The movement problems in PD and in these rats occur due to a reduction of an enzyme called TH which is essential for dopamine production. We have discovered that SRY can regulate TH in human dopamine-producing cells. This project aims to understand at the molecular level how SRY controls TH. Secondly SRY protein levels will be investigated in men with PD to test the hypothesis that lower TH levels are a consequence of lower SRY levels in PD men. This would implicate SRY as a contributing factor in increased susceptibility of men to PD. 2. The Sox9 knockout mouse: A mouse model for Disorders of Sexual Development Supervisors: Dr Stefan Bagheri-Fam and Associate Professor Vincent Harley In mammals, sex is determined in the bipotential foetal gonad by a balanced network of protein interactions. If this network is altered Disorders of Sexual Development (DSD, formerly known as intersex) can arise. Human mutations in SOX9 cause male-to-female sex reversal in XY individuals. Using the Cre-loxP recombination technology we have conditionally inactivated Sox9 in the gonad in mice. This has allowed us to follow the fate of sex reversed Sox9 -/-XY gonads in vivo throughout gonadal formation during embryogenesis. These gonads will be analysed by immunohistochemistry, in situ hybridisation and RT-PCR to investigate the molecular consequences of the loss of Sox9. This project will also include a microarray analysis of the XY Sox9 knockout gonad targeted at the identification of genes involved in testis formation. 3. The role of SOX9 in craniofacial development Supervisors: Dr Stefan Bagheri-Fam and Associate Professor Vincent Harley 4. Functional characterisation of the chromatin-remodelling protein, ATRX Supervisors: Dr Anthony Argentaro and Associate Professor Vincent Harley The ATR-X syndrome is a severe developmental disorder resulting in a mental retardation, characteristic facial and skeletal abnormalities, alpha thalassaemia and urogenital abnormalities. The ATRX protein comprises two highly conserved domains; a N-terminal PHD-like domain and a C-terminal helicase-like domain which shares homology to the SNF2 family of chromatin remodelling proteins. The functional importance of these domains is highlighted by the fact that the majority of the clinical mutations are located within these domains. Mutations which arise in a third domain located in the extreme C-terminus almost always results in complete XY sex reversal in patients suggesting that this region plays an important role in urogenital development. Two project areas are on offer in understanding the role of ATRX in urogenital development 1) identifying and characterising proteins which interact with the C-terminal domain of the ATRX protein and 2) characterisation of mice lacking ATRX. 5. Functional analysis of miRNAs in the developing testis Supervisors: Dr Stefan Bagheri-Fam and Associate Professor Vincent Harley MicroRNAs (miRNAs) are critical regulators of transcriptional and post-transcriptional gene silencing, which are involved in multiple developmental processes in many organisms. Over 100 miRNAs have been found in the mouse testis; however the function of these miRNA during testicular development is unclear. This project aims to analyse the role of miRNA biogenesis in testis development by using conditional Dicer-knockout mice in which Dicergene will be deleted specifically in the testis. The Sunday Age 19 March 2006, "Bright Minds, Big City" New Scientist. Oct 27, 2008. Male-to-female transsexualism gene found Holden, C. "Gender and the Brain" Science 322: 831 (November 7, 2008) Australian Life Scientist article "Polymorphism link in transsexualism" (6 February 2009) Holden, C. "Thinking ‘Bout Sex" ScienceNOW Daily News. (February 21,2006) |
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Human Molecular Genetics
