Body Segment Identity Specification By The Transcription Regulator, Moz
Funder
National Health and Medical Research Council
Funding Amount
$366,301.00
Summary
One in 28 newborns have birth defects. Cleft palate and aortic arch defects are among the most common, always requiring surgery and often causing lethality. We propose to study a protein, Moz, which is essential for palate and aortic arch development. Moz (Monocytic leukaemia zinc finger protein) was first identified in human chromosomal abnormalities causing particularly aggressive forms of childhood and adult leukaemia. We have shown previously that Moz is essential for the formation of blood ....One in 28 newborns have birth defects. Cleft palate and aortic arch defects are among the most common, always requiring surgery and often causing lethality. We propose to study a protein, Moz, which is essential for palate and aortic arch development. Moz (Monocytic leukaemia zinc finger protein) was first identified in human chromosomal abnormalities causing particularly aggressive forms of childhood and adult leukaemia. We have shown previously that Moz is essential for the formation of blood stem cells. Moz can regulate the activity of genes, but which genes it regulates in vivo is unknown. In the absence of Moz, mice are born with a cleft palate, lack the thymus, where immune cells are instructed, and fail to form the lung blood circulation, so that they are unable to supply their blood with oxygen after birth. Moz deficiency also causes defects of the vertebrate column, such that individual vertebrae acquire the appearance of their neighbours. These symptoms are typical for a general defect in positional information of individual body segments with respect to their location along the body axis. We will investigate the molecular mechanisms that require Moz in patterning of the body axis. This project will characterize a genetic mechanism that is crucial for normal development of the palate, the aorta and the vertebrate column.Read moreRead less
My background is in the study of human molecular genetic disease, and my interest has evolved to the analysis of embryonic development using the mouse as a model system. My particular interest is in the molecular mechanisms governing limb and craniofacial
Nfi Genes Regulate The Switch Between Neurogenesis And Gliogenesis During Cortical Development
Funder
National Health and Medical Research Council
Funding Amount
$387,489.00
Summary
Cells within the brain fall into two categories; neurons or glia. Importantly, both derive from a common progenitor population, the radial glia, during development. Early in development radial glia produce neurons, while later they generate glia. The genes which control the switch from neuron production to glia production remain poorly defined. I propose to investigate how this switch is controlled in radial glia, focussing on a family of proteins known to regulate gene transcription.
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
Truncating Presenilin Mutations And Their Effects On Gamma-secretase Activity, Tau And Beta-catenin
Funder
National Health and Medical Research Council
Funding Amount
$414,005.00
Summary
Alzheimer's disease (AD) and cancer are increasingly important both in terms of human suffering and the burden of care it imposes on society and the economy. Sporadic (non-inherited) AD is the most common form of dementia but is poorly understood. The PRESENILIN genes, PSEN1 and PSEN2, are the major sites for mutations causing inherited AD and are also implicated in cancer. Using the zebrafish embryo model we have discovered that, contrary to current thought, mutations that truncate presenilin p ....Alzheimer's disease (AD) and cancer are increasingly important both in terms of human suffering and the burden of care it imposes on society and the economy. Sporadic (non-inherited) AD is the most common form of dementia but is poorly understood. The PRESENILIN genes, PSEN1 and PSEN2, are the major sites for mutations causing inherited AD and are also implicated in cancer. Using the zebrafish embryo model we have discovered that, contrary to current thought, mutations that truncate presenilin proteins potently suppress normal presenilin activity. (They are so called, dominant negatives). This means that they are lethal for embryo development and explains why such mutations have never been found in inherited AD. Notably, this discovery could only be made using a subtle form of gene manipulation that is possible in zebrafish embryos. Our work has also established the first assay for the non-apoptotic (non-cell death) function of PSEN2 and has shown that PSEN2 activity is inhibited by truncated PSEN1. This is the first indication of possible interaction between PSEN1 and PSEN2 proteins at normal physiological expression levels. Loss of presenilin activity promotes cancer. Truncated presenilin proteins could be produced by errors in gene transcription (aberrant transcript splicing) common in cancerous cells. This suggests that truncated, dominant negative forms of presenilin produced through aberrant splicing (or mutation in precancerous cells) might be common in tumour formation. The proposed research will define the region of PSEN1 in which truncation leads to dominant negative activity. This will allow further examination of the role of presenilins in the cell signalling pathways involved in AD and cancer. We will also investigate the role that age-related truncation of presenilins in human cells can play in the formation of sporadic AD. This may reveal a common molecular link between the inherited and sporadic forms of this disease.Read moreRead less
The Role Of GRHL-3, A Mammalian Homologue Of Drosophila Grainyhead, In Neural Tube Development
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Spina bifida and anencephaly are two common human congenital malformations that form part of a wide spectrum of mutations known collectively as neural tube defects (NTDs). Patients with the most severe form of spina bifida have a failure of the vertebral column and skin to close over the spinal cord and therefore suffer from limb paralysis and marked bladder and bowel dysfunction. Infants with anencephaly have an open cranial vault and failure of normal brain development and die within the first ....Spina bifida and anencephaly are two common human congenital malformations that form part of a wide spectrum of mutations known collectively as neural tube defects (NTDs). Patients with the most severe form of spina bifida have a failure of the vertebral column and skin to close over the spinal cord and therefore suffer from limb paralysis and marked bladder and bowel dysfunction. Infants with anencephaly have an open cranial vault and failure of normal brain development and die within the first few hours of life. These abnormalities occur frequently (1-1000 live births) and are a direct result of failure of the neural tube to close during embryogenesis. NTDs are influenced by both environmental and genetic factors. The best characterised environmental factor is the dietary supplement folate, which when administered before conception results in a reduction in the incidence of spina bifida. The genetic complexity is evidenced by the array of mouse genetic mutations that give rise to NTDs. One of these mouse mutations, known as Curly tail (ct), has served as the major animal model of human NTDs. This is because the ct mice are resistant to folate administration (like most of the cases of spina bifida currently seen in patients) and because the mice seem to have normal development in virtually all other organ systems. Ironically, the genetic mutation that causes the curly tail phenotype has remained undiscovered for over 50 years. We have now identified the gene mutated in the curly tail mice. This gene is highly conserved in humans suggesting that it will play a similar role in neural tube development in man. The gene, known as GRHL-3, is a descendant of a fly gene critical for development of the nervous system in that organism. The studies we propose here will examine the developmental pathways involved in normal neural tube closure in mice and humans and will impact on our understanding of these devastating congenital malformations.Read moreRead less
Interactions Between Hedgehog And Ras Signaling In Lung Adenocarcinoma
Funder
National Health and Medical Research Council
Funding Amount
$295,983.00
Summary
Lung cancer is a common and lethal disease in our community. In this project, we explore how signaling pathways that regulate the development of the lung in embryos contribute to the initation and progression of lung cancer. To do this, we use a mouse model of lung cancer in which we can activate embryonic signaling pathways in adult mice to study there effect on the disease. Understanding these pathways will help us to better treat and prevent lung cancer in humans.
Functional Analysis Of The Notch Signalling Pathway In The Differentiation And Maintenance Of Pituitary Progenitor Cells
Funder
National Health and Medical Research Council
Funding Amount
$421,320.00
Summary
Many of the processes that are essential for normal bodily function such as growth, the ability to cope with stress, sexual organ development, metabolism and milk production, are controlled by the pituitary gland. This organ is located at the base of the brain and regulates these bodily functions through the release of six different hormones. Formation of the pituitary gland occurs during development of the foetus. This process requires a specific set of genes that shape the pituitary and allow ....Many of the processes that are essential for normal bodily function such as growth, the ability to cope with stress, sexual organ development, metabolism and milk production, are controlled by the pituitary gland. This organ is located at the base of the brain and regulates these bodily functions through the release of six different hormones. Formation of the pituitary gland occurs during development of the foetus. This process requires a specific set of genes that shape the pituitary and allow the hormone secreting cells to arise. Changes in these pituitary formation genes results in underdevelopment of the pituitary in newborn babies. In severe cases, where the pituitary has failed to form completely (panhypopituitarism), these babies are extremely ill and in some instances do not survive. We are studying the genes that belong to the Notch signalling pathway. These genes are important regulators of cell differentiation during the development of the brain, skin, bone and many other tissues. However, the role of the Notch signalling genes in pituitary development is not known. We have shown for the first time that these genes are active during pituitary development. To test the function of these genes in the pituitary, we will generate mouse models that either lack or inappropriately activate these genes. Our results will provide insight into the role of Notch Signalling genes in pituitary development in mice and humans. In this project, we also hope to identify cells in the pituitary that are able to give rise to multiple hormone secreting cell types. These stem cells are of significant clinical importance as they provide an avenue for the development of novel therapies for pituitary disorders in humans, based on the replacement of defective pituitary tissue with functional stem cell derived tissue.Read moreRead less