A Y CHROMOSOME MODEL FOR THE SEX DETERMINING FUNCTION OF THE HUMAN ATRX GENE
Funder
National Health and Medical Research Council
Funding Amount
$272,131.00
Summary
Human sex determination is controlled by a genetic pathway which culminates in the development of a testis or an ovary in the human embryo. At the head of this pathway is the master switch gene SRY on the Y chromosome, which controls a cascade of other genes critical for switching on testis development. Several other genes have been identified by clinical mutations which reverse sex of XY embryos. One sex reversing gene is ATRX on the human X chromosome. Mutation in ATRX causes XY embryos to dev ....Human sex determination is controlled by a genetic pathway which culminates in the development of a testis or an ovary in the human embryo. At the head of this pathway is the master switch gene SRY on the Y chromosome, which controls a cascade of other genes critical for switching on testis development. Several other genes have been identified by clinical mutations which reverse sex of XY embryos. One sex reversing gene is ATRX on the human X chromosome. Mutation in ATRX causes XY embryos to develop as females, as well as causing many unrelated disorders such as alpha-thalassemia. ATRX seems to be a transcription factor that controls the activity of other genes, but it is difficult to understand how it functions because it is active in all parts of the body and mutation has many different effects in humans. However, we recently discovered that in marsupial mammals that this gene has a copy on the Y chromosome (ATRY) as well as the X (ATRX). Remarkably, there is a division of labour between ATRY, which acts only in developing gonads, and ATRX, which is active everywhere else. This testis-specific ATRY gene may reveal how ATRX interacts with other genes to make a testis, without the complications of its action in other tissues. We will therefore clone and characterize ATRX-Y and its protein product to find out when and where it acts in the sex determining pathway. We will use very large cloned pieces of the marsupial genome to discover elements controlling the testis-specific expression, and we will identify the interactions of ATRY with other proteins. The testis determination pathway is a good model for the differentiation of other human organs. Our work on ATRY will show us how this class of transcription factors is activated in different tissues during development, and how it controls other genes. This will lead to a better understanding of the genetic control of human organogenesis and the effects of mutation on human development.Read moreRead less
How Important Is Collagen Destruction In Arthritis? A Study With Collagenase-resistant Knockin Mice
Funder
National Health and Medical Research Council
Funding Amount
$529,723.00
Summary
Aggecan and collagen are important structural molecules in cartilage. Together they allow cartilage to bear weight and resist compression. In arthritis, collagen is degraded by collagenases and aggrecan is degraded by aggrecanases. Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well documented and usually precedes clinical symptoms, suggesting that it is the initiating step in cartilage pathology. Aggrecan loss precedes collagen damage in explant culture, however it is n ....Aggecan and collagen are important structural molecules in cartilage. Together they allow cartilage to bear weight and resist compression. In arthritis, collagen is degraded by collagenases and aggrecan is degraded by aggrecanases. Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well documented and usually precedes clinical symptoms, suggesting that it is the initiating step in cartilage pathology. Aggrecan loss precedes collagen damage in explant culture, however it is not known whether inhibiting aggrecanases is sufficient to block cartilage damage long-term. In contrast, other studies suggest that aggrecan is only lost after damage to the collagen scaffold. These studies propose that clipping of the collagen scaffold may initiate aggrecan release; with progressive degeneration and collagen clipping, more aggrecan is lost, until ultimately the scaffold is severely damaged and aggrecan is severely depleted. Cartilage can only withstand a limited degree of collagen degradation and any significant damage to the network is widely considered to be irreparable. It is unclear what role aggrecanases and collagenases have in initiating and perpetuating cartilage damage. We have mice with aggrecan resistant to aggrecanases and mice with inactive aggrecanase. We will also create mice with collagen resistant to collagenase. We will use these mice to determine the contribution of collagenases and aggrecanases to the initiation and progression of cartilage damage, in three models of joint disease. We will identify differences in time of disease onset, rate of disease progression and disease severity. The results will show whether one or both activities is important for the initiation and progression of joint disease. This will reveal whether single or combination therapies are required for the management of arthritis. The research will inform the pharmaceutical industry on directions for the development of new drugs to prevent joint disease.Read moreRead less
Cellular And Molecular Determinants Of Preleukaemic And Leukaemic Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$292,635.00
Summary
It has recently become evident that the formation, growth and relapse of many cancers is driven by a rare population of cancer stem cells (CSCs) that have the unique ability to propagate new tumours and are highly resistant to current therapies. However, which normal cells are transformed into CSCs is not known. We will take a potent cancer gene found in leukaemia, and switch it on and off in specific blood cells in mice to determine which healthy cells can be turned into leukaemic stem cells.