Identification Of Genes Important In Myeloid And Haemopoietic Development By Genetic Screening In Zebrafish
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
Zebrafish have emerged as a powerful experimental model in developmental genetics. Their favourable attributes include their reproductive biology, the optical clarity of embryos, and the accessibility of embryos for experimental procedures. Previous studies overseas have recovered over 1500 strains of zebrafish with inherited diseases due to induced mutations in about 500 genes. Many of these zebrafish have abnormalities of unexpected precision and are leading to new genes with novel specialized ....Zebrafish have emerged as a powerful experimental model in developmental genetics. Their favourable attributes include their reproductive biology, the optical clarity of embryos, and the accessibility of embryos for experimental procedures. Previous studies overseas have recovered over 1500 strains of zebrafish with inherited diseases due to induced mutations in about 500 genes. Many of these zebrafish have abnormalities of unexpected precision and are leading to new genes with novel specialized functions. About 50 mutant zebrafish strains exist in which red blood cell development is perturbed - this was easily recognized because the transparency of embryos enabled lack of blood be easily seen. Our new studies aim primarily to recover mutant zebrafish with disorders of white blood cell formation. We have identified methods to recognize failure of white blood cell formation in zebrafish, and will employ these methods to look for inherited disorders that specifically affect white blood cell development in a process called genetic screening. Fish with different sets of randomly mutated genes will be systematically screened to identify those with abnormal white blood cell development. We have tested our approach and identified several mutants affecting white blood cell development. Once these new strains of fish are identified, we will find the genetic lesion responsible for the abnormality in several of the most interesting strains by gene mapping and positional cloning. Hence, the mutant zebrafish identified in the screen will eventually lead to the discovery of new genes important in white blood cell growth and development. The fish themselves will provide insights into the causes of congenital diseases of white blood cells. Since many genes involved in early development are also important in cancer, we believe that newly identified genes will also help understand the causes of abnormal growth of white blood cells in leukaemia.Read moreRead less
A knockout approach to identifying genes involved in epidermal development and homeostasis. These studies will identify new genes which play a role in the development or maintenance of the skin, some of which may subsequently be shown to play a role in disease. The project capitalises on an investment of tens of millions of dollars by the Wellcome Trust in generating a significant cohort of knockout mice. Our involvement in this international initiative will ensure Australia's participation in ....A knockout approach to identifying genes involved in epidermal development and homeostasis. These studies will identify new genes which play a role in the development or maintenance of the skin, some of which may subsequently be shown to play a role in disease. The project capitalises on an investment of tens of millions of dollars by the Wellcome Trust in generating a significant cohort of knockout mice. Our involvement in this international initiative will ensure Australia's participation in a project at the forefront of mouse genetics, using cutting edge infrastructure and technologies to provide insights into the complement of genes involved in skin biology. Models of interest will be repatriated to Australia for further study capitalising on existing infrastructure provided through the NCRIS funding program. Read moreRead less
Actin cytoskeleton regulation by E-cadherin and Src. This project examines a fundamental, novel mechanism of how cells work together in tissues. It will provide important new knowledge about how tissues become organized in health, and how organization might be disturbed in disease. It will build Australia's skill base in cutting-edge scientific research, and promote knowledge directed to the research priority area of Promoting and Maintaining Good Health.
How the Y Chromosome makes a male: Molecular genetic analysis of key sex-determining genes. Sex reversal and intersex syndromes are among the most common and highly stigmatized disorders affecting newborn babies. Our research will reveal how the Y chromosome regulates normal male development, identify the steps that go wrong in many male babies, and suggest ways to diagnose and deal with these conditions. It will also pave the way for biotechnological applications in the areas of stem cell techn ....How the Y Chromosome makes a male: Molecular genetic analysis of key sex-determining genes. Sex reversal and intersex syndromes are among the most common and highly stigmatized disorders affecting newborn babies. Our research will reveal how the Y chromosome regulates normal male development, identify the steps that go wrong in many male babies, and suggest ways to diagnose and deal with these conditions. It will also pave the way for biotechnological applications in the areas of stem cell technology, pest management, wildlife conservation and animal breeding.Read moreRead less
MOLECULAR GENETICS OF MAMMALIAN SEXUAL DEVELOPMENT: Molecular roles of SRY and SOX9. The development of sexual characteristics is critical to the survival of almost all animal species. This project seeks to clarify how male and female embryos develop differently, focusing on the Y-chromosome maleness gene Sry, and a closely related and equally important gene Sox9. We will study how these genes are switched on in developing gonads and how they interact with other genes to bring about testis forma ....MOLECULAR GENETICS OF MAMMALIAN SEXUAL DEVELOPMENT: Molecular roles of SRY and SOX9. The development of sexual characteristics is critical to the survival of almost all animal species. This project seeks to clarify how male and female embryos develop differently, focusing on the Y-chromosome maleness gene Sry, and a closely related and equally important gene Sox9. We will study how these genes are switched on in developing gonads and how they interact with other genes to bring about testis formation in male embryos. In this way we will discover new genes and mechanisms that are important for sexual identity and also other aspects of embryo development.Read moreRead less
Insect development : the role of cytochrome P450s. Pest insects vector human diseases such as malaria and impose a massive burden in agriculture due to control costs and production losses. The intelligent control of insect pests requires an understanding of their development that is controlled by hormones. This project will provide an in depth understanding of insect hormone synthesis/degradation that is controlled by a class of enzymes, the cytochrome P450s. This will increase the potential ....Insect development : the role of cytochrome P450s. Pest insects vector human diseases such as malaria and impose a massive burden in agriculture due to control costs and production losses. The intelligent control of insect pests requires an understanding of their development that is controlled by hormones. This project will provide an in depth understanding of insect hormone synthesis/degradation that is controlled by a class of enzymes, the cytochrome P450s. This will increase the potential for new insect-specific control strategies with a decreased environmental impact.Read moreRead less
A new paradigm of gene regulation - implications in embryogenesis and disease. The proposed analysis of a new paradigm of gene regulation will provide a new key to understanding genome function and inform some of the most compelling biological issues of our time such as stem cell biology, tissue and organ regeneration and genetic programming. The insights and technologies developed in this program will be widely applicable in biotechnological and pharmacogenomic research in Australia and worldwi ....A new paradigm of gene regulation - implications in embryogenesis and disease. The proposed analysis of a new paradigm of gene regulation will provide a new key to understanding genome function and inform some of the most compelling biological issues of our time such as stem cell biology, tissue and organ regeneration and genetic programming. The insights and technologies developed in this program will be widely applicable in biotechnological and pharmacogenomic research in Australia and worldwide, and assert Australia's leadership in this area of research.Read moreRead less
Evolution in microsatellite DNA: testing models of mutation in an Australian marsupial. We aim to compare mutational events between microsatellite loci that vary in their exposure to recombination. We are able to do this because of a remarkable finding that Australian brushtail possums have multiple occurrences of a single microsatellite repeat element within the Y-chromosome and among autosomal loci. We will compare variation between the Y-linked and non Y-linked loci within and among individu ....Evolution in microsatellite DNA: testing models of mutation in an Australian marsupial. We aim to compare mutational events between microsatellite loci that vary in their exposure to recombination. We are able to do this because of a remarkable finding that Australian brushtail possums have multiple occurrences of a single microsatellite repeat element within the Y-chromosome and among autosomal loci. We will compare variation between the Y-linked and non Y-linked loci within and among individual possums and use those comparisons to distinguish between recombinant and non- recombinant mutational mechanisms. These data will provide new insights into the mutational mechanisms that drive variation in these most important molecular markers.Read moreRead less
Sex in Dragons: Evolution of sex determination in reptiles. Australia is a leader in sex determination research with major advances in our understanding attributable to Australian researchers and laboratories. This project will contribute to our prestige as a nation capable of contributing cutting edge research directions and stimulating ideas in human sex determination. Moreover, many reptiles have temperature-dependent sex determination, and so would appear appallingly vulnerable to climate ch ....Sex in Dragons: Evolution of sex determination in reptiles. Australia is a leader in sex determination research with major advances in our understanding attributable to Australian researchers and laboratories. This project will contribute to our prestige as a nation capable of contributing cutting edge research directions and stimulating ideas in human sex determination. Moreover, many reptiles have temperature-dependent sex determination, and so would appear appallingly vulnerable to climate change. Our project, will bring improved understanding of sex determination in reptiles, identify evolutionary responses of reptiles to climate change, and assist by informing society on how we might manage this issue into the future conservation of these unique Australian reptiles. Read moreRead less
Lungfish Paired Fins and the Origin of Limbs as an Evolutionary Novelty. This project will utilise a uniquely Australian animal, the lungfish, to address a hitherto unresolved problem of considerable scientific significance - how a fish fin evolved into a tetrapod (four-legged animal) limb. The Australian lungfish is the most primitive of the four surviving genera of lobe-finned fish and is recognised as the closest living ancestor to the tetrapods. It is listed as 'vulnerable' in its native ha ....Lungfish Paired Fins and the Origin of Limbs as an Evolutionary Novelty. This project will utilise a uniquely Australian animal, the lungfish, to address a hitherto unresolved problem of considerable scientific significance - how a fish fin evolved into a tetrapod (four-legged animal) limb. The Australian lungfish is the most primitive of the four surviving genera of lobe-finned fish and is recognised as the closest living ancestor to the tetrapods. It is listed as 'vulnerable' in its native habitat. Macquarie University, however, has the only captive breeding population of lungfish in the world. We are thus uniquely placed to address critically important questions concerning the evolution of fish into tetrapods. Read moreRead less