Retrotransposons As Controlling Elements In Mammals: A Screen For Expression In Somatic Cells And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$452,545.00
Summary
Differences between individual mammals are generally thought to be due to differences either between their genes, or between their environments. However, in many cases genetic or environmental factors cannot account for differences between individuals. We have studied mice in which dramatic differences between genetically identical individuals are due solely to the activity of a type of transposable element (transposon). There are tens of thousands of similar elements in the genomes of all mamma ....Differences between individual mammals are generally thought to be due to differences either between their genes, or between their environments. However, in many cases genetic or environmental factors cannot account for differences between individuals. We have studied mice in which dramatic differences between genetically identical individuals are due solely to the activity of a type of transposable element (transposon). There are tens of thousands of similar elements in the genomes of all mammals. A large body of evidence demonstrates that transposons can disrupt gene expression. To prevent this from occurring, most organisms have evolved mechanisms to keep transposons silent. However, fragmentary evidence indicates that transposons are at least sometimes expressed in normal and cancer cells. We hypothesize that activity of transposons in mammals alters gene expression sufficiently to cause variation between individuals, and that altered gene expression can cause disease (particularly cancer) and some manifestations of aging. As a first step toward testing this hypothesis, it is essential to acquire more complete information on the expression of transposons in normal and diseased cells. Furthermore, if transposon expression is closely linked to the development or progression of cancer or aging, then the ability to monitor such expression could have diagnostic utility. DNA array technology is coming into wide use to compare patterns of gene expression in different types of cells. We propose to adapt this method to the study of transposon expression. We will clone examples of all known classes of mouse and human transposon, and study transposon expression in: 1. Normal mice, at intervals from the earliest phase of development to old age, and 2. Human cancers of a variety of types. These studies will provide information of fundamental significance for mammalian biology, and also have the potential to lead to improved diagnosis of disease.Read moreRead less
Understanding Human Dysmorphology Through Analysis Of ENU Mutant Mice
Funder
National Health and Medical Research Council
Funding Amount
$602,501.00
Summary
Birth defects are common and have an enormous impact on both the individual and their family. Birth defects are by definition the products of abnormal development of the embryo. Our research is aimed at identifying the normal mechanisms that usually prevail during development and the disturbances to those mechanisms that result in birth defects. These findings will lead to improved diagnostic, therapeutic and preventative options for families affected by birth defects
Rapid Identification And Characterisation Of Genes Involved In Skeletal Development
Funder
National Health and Medical Research Council
Funding Amount
$550,536.00
Summary
Birth defects are common and have an enormous impact on both the individual and their family. Birth defects are by definition the products of abnormal development of the embryo. Our research is aimed at identifying the normal mechanisms that usually prevail during development and the disturbances to those mechanisms that result in birth defects. These findings will lead to improved diagnostic, therapeutic and preventative options for families affected by birth defects
The Role Of Netrin-DCC In The Development Of The Corpus Callosum
Funder
National Health and Medical Research Council
Funding Amount
$512,065.00
Summary
During embryonic development neurons send out axons that connect to other target neurons within the brain. The proper connectivity of these axons is vital to brain function. The largest axon tract in the brain is called the corpus callosum and connects neurons in the left and right cerebral hemispheres. When the corpus callosum does not form, significant cognitive, motor and sensory deficits occur in patients. This condition, known as agenesis of the corpus callosum (ACC), is associated with ove ....During embryonic development neurons send out axons that connect to other target neurons within the brain. The proper connectivity of these axons is vital to brain function. The largest axon tract in the brain is called the corpus callosum and connects neurons in the left and right cerebral hemispheres. When the corpus callosum does not form, significant cognitive, motor and sensory deficits occur in patients. This condition, known as agenesis of the corpus callosum (ACC), is associated with over 50 different human congenital syndromes. Thus understanding how the genes and molecules involved in the formation of the corpus callosum function in normal development can provide the basis for our understanding of what goes wrong in ACC. In this proposal we will investigate the role of the axon guidance molecule Netrin1, and its receptor DCC, in development of the corpus callosum in both a mouse model and in humans with malformations of the corpus callosum. Although Netrin1-DCC signalling has traditionally been associated with mechanisms of axon guidance, we hypothesize that these molecules may play a different role, specifically in cellular adhesion and ultimately in the fusion of the two cerebral hemispheres, in a manner that allows the corpus callosum to form. A second role for Netrin1-DCC signalling may be in the guidance of these axons once the midline has fused correctly and we investigate this in Aim 2 of the proposal. Finally, we are collaborating with a paediatric neurologist at UCSF, who has identified several mutations in the DCC gene in patients with ACC. In Aim 3 we test whether these mutations disrupt the function of DCC in callosal axon pathfinding. Understanding how these genes function during development of the brain and how their function may be altered in ACC is crucial to providing a proper diagnosis and prognosis for these patients. Ultimately, understanding more about how these genes function could also lead to prevention of these disorders.Read moreRead less
Impact Of The Extraembryonic Tissues On Early Embryonic Development: Genetic Basis Of Abnormal Body Plan
Funder
National Health and Medical Research Council
Funding Amount
$316,326.00
Summary
An important milestone of early development is the attachment (or implantation) of the embryo to the wall of the womb through the action of a specialized population of cells known as the trophoblasts. The early conceptus comprises not only cells that make up the embryo but also those (called extraembryonic cells) that later forms the placenta, and the membranes that wrap around the developing fetus. The placenta and the membranes are indispensable for the normal fetal growth by providing the eff ....An important milestone of early development is the attachment (or implantation) of the embryo to the wall of the womb through the action of a specialized population of cells known as the trophoblasts. The early conceptus comprises not only cells that make up the embryo but also those (called extraembryonic cells) that later forms the placenta, and the membranes that wrap around the developing fetus. The placenta and the membranes are indispensable for the normal fetal growth by providing the effective nourishment and protection for the developing fetus. Recent studies in the mouse have revealed that normal development of the recently implanted conceptus depends on the reciprocal interaction of the embryonic and extraembryonic cells. Abnormal embryo may form if the non-embryonic cells do not differentiate normally, as seen in the situation when an X-chromosome is lost from the female embryo (as in 45X0 Turner syndrome) and in early conceptus that carries a gene mutation that affects the production of growth factors by the extraembryonic cells. Functional deficiency of the extraembryonic cells might be a cause for early pregnancy loss where the conceptus has successfully implanted but the embryo fails to form. The remarkable conservation of the molecular mechanism that controls mammalian development allows us to use the mouse embryo as a genetic model for human development. The proposed project is designed to examine in a laboratory mouse model the molecular and cellular factors that regulate the activity of the extraembryonic cells. Specifically, we focus on a gene known as Sox17, which may be involved with the differentiation of the extraembryonic cells. We will study the impact of the mutation of this gene on the development of the early embryo to test the hypothesis that the extraembryonic cells may fulfill an important function in ensuring normal embryo formation, in addition to the other roles of nourishment and mechanical protection of the fetus.Read moreRead less
Copy Number Analysis Of Patients With Gonadal Abnormalities Using High Density Microarrays And MLPA
Funder
National Health and Medical Research Council
Funding Amount
$311,187.00
Summary
Congenital conditions in which development of the gonads or anatomical sex is abnormal are surprisingly common. The underlying cause of these problems is most often the failure of genes responsible for proper development of testes or ovaries. Only a small proportion of patients can be explained by mutations in known gonad determining genes. We will analyse DNA from these patients on very high density microarrays to identify new genes that cause abnormalities in testis and ovary development.
Relating Genetic, Biological, And Behavioural Markers Of Early Conduct Problems In Young Females
Funder
National Health and Medical Research Council
Funding Amount
$403,639.00
Summary
Child CPs are the first identifable sign of ongoing mental health problems. Most research is done with males, but they are also the most common early markers in females. We are in the unique position to conduct the first test of the relationships between specific genetic risk, neurobiological markers and psychological functioning in females. Findings will inform models of genertic vulnerability, the relationship of genetic risk to basic information processing styles in at-risk children.
Relating Genetic, Biological, And Behavioural Markers Of Early Vulnerability In Conduct Problem Children.
Funder
National Health and Medical Research Council
Funding Amount
$439,183.00
Summary
This research will conduct the first test of specific genetic risk in a large and representative sample of young conduct problem children. These children represent the first readily identifiable group that are at high risk for ongoing mental health problems in our community. It is highly likely that within their numbers are heterogeneous subgroups that will take very different trajectories through life. The current study builds on several years of developmental research in which we have develope ....This research will conduct the first test of specific genetic risk in a large and representative sample of young conduct problem children. These children represent the first readily identifiable group that are at high risk for ongoing mental health problems in our community. It is highly likely that within their numbers are heterogeneous subgroups that will take very different trajectories through life. The current study builds on several years of developmental research in which we have developed methods for identifying different phenotypes within the group. The study will identify genetic markers of these subtypes and relate these to emotional processing as a general model of risk in the development of mental health problems and antisocial behaviour. Findings will inform models of genetic vulnerability, and more importantly, the relationship of genetic risk to basic information processing styles in at-risk children, thus aiding methods for early detection, early intervention and prevention.Read moreRead less
Analysis Of The Function Of The Presenilin Genes During Embryogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$197,317.00
Summary
The presenilin genes are essential for normal human mental health. Deleterious changes in presenilin genes are the root cause of 60% of Alzheimers Disease that is inherited within families (ie. Oearly onsetO Alzheimers disease) and of 10% of all Alzheimers disease. Normal presenilin genes are also necessary for correct embryo development. There is evidence that the proteins produced by the presenilin genes interact with other proteins such as those produced by the Notch genes. Changes in Notch g ....The presenilin genes are essential for normal human mental health. Deleterious changes in presenilin genes are the root cause of 60% of Alzheimers Disease that is inherited within families (ie. Oearly onsetO Alzheimers disease) and of 10% of all Alzheimers disease. Normal presenilin genes are also necessary for correct embryo development. There is evidence that the proteins produced by the presenilin genes interact with other proteins such as those produced by the Notch genes. Changes in Notch genes can also produce dementia and developmental defects. However, despite their obvious importance, we know little about how presenilin and Notch genes function and interact! We want to understand how presenilin genes interact with Notch genes and any other genes that are important for normal embryo development. To investigate this we are using the eggs of a small, freshwater fish, the zebrafish. These eggs are easily available (hundreds are produced by a female zebrafish every week), accessible and, being transparent, every cell in a developing zebrafish egg can be observed! They also develop about one hundred times faster that a human! In our experiments we will produce antibodies to the protein products of the presenilin and Notch genes of zebrafish and then use these to observe interactions between the presenilin and Notch proteins. We will observe how changes in the levels of presenilin protein in an embryo affect the function of the Notch genes and we will attempt to discover other genes that are affected by such changes. This work will be important for understanding how genes interact to create our bodies during embryo development. Also, since genes typically interact in similar ways during embryo development and in adults, the discoveries that we make will help us to understand what goes wrong when changes in the presenilin genes cause Alzheimers disease.Read moreRead less