Genetics Of Intersex: Antagonism Between Male And Female Pathways During Gonadal Development
Funder
National Health and Medical Research Council
Funding Amount
$567,760.00
Summary
Disorders of sex Development (DSD) are congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical. Estimates suggest that between 1-100 and 1-300 live birth have DSD; however, the underlying genetic defect is unknown in 80% of cases. Generally, the fate of the gonad, testis or ovary, is determined by the balanced action of male (SRY) and female (Wnt- b-catenin) genes. How do these genes oppose each other? Is this antagonism deregulated in DSD patients?
A bird's eye view of sex: the chicken embryo as a model for gonadal development. The development of an embryo as either male or female (sex determination) is a fundamental biological process that fascinates both scientific and lay communities alike. This project will use the chicken embryo as a unique model organism to study how genes control sex determination. We will bring a novel method to our field of study; the use of avian viruses to deliver genes into embryos. This project will enhance ou ....A bird's eye view of sex: the chicken embryo as a model for gonadal development. The development of an embryo as either male or female (sex determination) is a fundamental biological process that fascinates both scientific and lay communities alike. This project will use the chicken embryo as a unique model organism to study how genes control sex determination. We will bring a novel method to our field of study; the use of avian viruses to deliver genes into embryos. This project will enhance our understanding of a basic biological process. It will have application to the poultry industry, in terms of sex ratio manipulation. It will also aid in the diagnosis of humans born with sexual abnormalities. The project will consolidate Australia's standing as a world leader in the area of reproduction and development.Read moreRead less
Disorders of sexual development are among the most common form of birth defects in humans (1 in 4,000 births) because failure of the gonads to develop does not affect the viability of the individual. Such disorders can have profound psychological and medical consequences upon the individual, family, and society. Some intersexual conditions are the result of inappropriate exposure to hormones during fetal life, and others are due to spontaneous or inherited gene mutation. About 5-10% of ovarian c ....Disorders of sexual development are among the most common form of birth defects in humans (1 in 4,000 births) because failure of the gonads to develop does not affect the viability of the individual. Such disorders can have profound psychological and medical consequences upon the individual, family, and society. Some intersexual conditions are the result of inappropriate exposure to hormones during fetal life, and others are due to spontaneous or inherited gene mutation. About 5-10% of ovarian cancer cases, that affect 1 in 8000 Australian women, are due to the inheritance of a faulty gene. An understanding of the way gene expression and hence tissue differentiation is altered after sex reversal will inform us about the causes and consequences of normal and abnormal sexual development, gonadal malignancies and infertility. The gonad is unusual in that two completely different organs can arise from an essentially identical primordium, so that errors in development lead to intersexual phenotypes. We will use our new experimental animal model to clarify these processes.Read moreRead less
I am a molecular biologist investigating the role of SRY-SOX transcription factors in the formation and function of the gonad, and to a lesser extent, of bone, the brain and the pancreas. I also identify and functionally characterise other factors causing
Deciphering genome function in animal development. The normal development of an embryo depends on complex and finely tuned gene regulatory mechanisms. In this Fellowship, I will use sophisticated new technologies to discover which of our 30,000 genes is important for embryonic development, reveal the roles of these genes, and identify the control mechanisms that can go awry to cause birth defects. Our research will suggest new ways to diagnose and deal with these conditions, and will be applicab ....Deciphering genome function in animal development. The normal development of an embryo depends on complex and finely tuned gene regulatory mechanisms. In this Fellowship, I will use sophisticated new technologies to discover which of our 30,000 genes is important for embryonic development, reveal the roles of these genes, and identify the control mechanisms that can go awry to cause birth defects. Our research will suggest new ways to diagnose and deal with these conditions, and will be applicable to stem cell technologies, tissue regeneration, cancer biology, conservation, pest management and livestock breeding, thus delivering significant economic and social benefits to Australia. Read moreRead less
Impairment of virilisation is one of the most common developmental defects in humans, yet over half the cases cannot be explained by our current knowledge. Studies of these processes is hindered because in most mammals virilisation occurs in the early fetus. Our recent studies using marsupials, where virilisation occurs after birth show that this process is mediated by 5-alpha-androstanediol, a hormone with previously undetermined physiological function. We will conduct experiments using tammar ....Impairment of virilisation is one of the most common developmental defects in humans, yet over half the cases cannot be explained by our current knowledge. Studies of these processes is hindered because in most mammals virilisation occurs in the early fetus. Our recent studies using marsupials, where virilisation occurs after birth show that this process is mediated by 5-alpha-androstanediol, a hormone with previously undetermined physiological function. We will conduct experiments using tammar wallabies and rabbits, to test 3 hypotheses about 5-alpha-androstanediol and specific enzymes in the developing reproductive tissues that either convert this hormone to active and inactive forms. The results of these experiments will direct testing for corresponding gene mutations in our collection of over 200 specimens from patients with defects of virilisation (pseudohemaphroditism) whose causes are still unknown. It is our expectation that the findings in these studies will provide insight not only into the pathways by which testicular hormones masculinize the developing male, but will also explain instances of male pseudohemaphroditism of unknown aetiology in humans.Read moreRead less
A shared genetic basis for development of the nervous system and glands. Fruit flies possess strikingly similar versions of the genes that promote normal human development. The list of systems with genetic parallels between humans and fruit flies includes the respiratory and circulatory systems; cardiovascular development and disease; sleep; learning and memory; brain development and disease; taste, sight, smell and hearing. This project could add at least some human glands, the mucous-secreting ....A shared genetic basis for development of the nervous system and glands. Fruit flies possess strikingly similar versions of the genes that promote normal human development. The list of systems with genetic parallels between humans and fruit flies includes the respiratory and circulatory systems; cardiovascular development and disease; sleep; learning and memory; brain development and disease; taste, sight, smell and hearing. This project could add at least some human glands, the mucous-secreting goblet cells, to this list, providing a potentially useful model for studying human diseases associated with gland dysfunction. Read moreRead less
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
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0561030
Funder
Australian Research Council
Funding Amount
$441,100.00
Summary
Developmental Imaging Facility. This application seeks to establish a facility to undertake expression profiling in vertebrate tissues on a genomic scale and at the highest resolution. Undertaking large scale projects of this nature requires specialised robotics and dedicated infrastructure for microscopy and tissue preparation. This facility will be the first of its type in Australia will permit researchers to perform genomic scale in situ screens, many as part of large international initiative ....Developmental Imaging Facility. This application seeks to establish a facility to undertake expression profiling in vertebrate tissues on a genomic scale and at the highest resolution. Undertaking large scale projects of this nature requires specialised robotics and dedicated infrastructure for microscopy and tissue preparation. This facility will be the first of its type in Australia will permit researchers to perform genomic scale in situ screens, many as part of large international initiatives in developmental and cellular biology. This large-scale, high-resolution expression profiling infrastructure is required to maintain international competitiveness and will dramatically improve our gene discovery, functional assessment and understanding of vertebrate development.Read moreRead less
Studying The Interaction Of Reelin Deficiency And Environmental Factors In The Development Of Schizophrenia Using Animal Behavioural Models
Funder
National Health and Medical Research Council
Funding Amount
$438,695.00
Summary
Schizophrenia is caused by an interaction of genetic predisposition and environmental risk factors such as stress or drug abuse. Reelin is a protein involved in the normal development of the brain but its levels are markedly reduced in schizophrenia. We will use mice with low levels of reelin in their brain and assess the effect of environmental stress and drugs of abuse. These studies could elucidate gene-environment interaction in schizophrenia and lead to new treatment strategies.