The Identification Of Genes Involved In Mammalian Craniofacial Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$408,055.00
Summary
Birth defects arising from abnormal development of the embryo are a major cause of infant mortality and childhood disabilities. On average 3-4% of liveborn babies have a major congenital abnormality, and of the 15-20% of pregnancies which spontaneously abort, many are due to chromosomal or other developmental anomalies. A common feature of many developmental disorders is dysmorphology of the face, suggesting that genes important in patterning the face are also important in the development of oth ....Birth defects arising from abnormal development of the embryo are a major cause of infant mortality and childhood disabilities. On average 3-4% of liveborn babies have a major congenital abnormality, and of the 15-20% of pregnancies which spontaneously abort, many are due to chromosomal or other developmental anomalies. A common feature of many developmental disorders is dysmorphology of the face, suggesting that genes important in patterning the face are also important in the development of other organ systems. During development of the embryo many of the features of the face derive from a series of swellings termed the pharyngeal arches. The complex processes which determine how the face develops are in a large part controlled by the co-ordinated expression of a large number of genes in the first two of the five pharyngeal arch pairs. While we know some of the genes involved in these processes, the precise mechanisms of craniofacial development are relatively poorly understood. In this project we propose a large scale approach to identifying genes involved in development of the mammalian face and to further delineating their role in development and human disease. This approach takes advantage of state of the art genomic technologies available at the IMB and through existing collaborations overseas. In collaboration with Dr Bento Soares (University of Iowa) we have constructed a library containing all of the genes which are expressed in the first two pairs of pharyngeal arches in the developing mouse embryo. Using an approach designed to eliminate all those genes which are expressed in all or most tissues of the body and play a general role in the body's metabolism, we will select for those genes which play a specific and important role in embryonic development. We will then isolate the human counterparts of these genes and more thoroughly investigate their role in embryonic development and disease.Read moreRead less
The Primary Cilium In Hedgehog Signalling And Disease
Funder
National Health and Medical Research Council
Funding Amount
$583,312.00
Summary
Every mammalian cell has a single protrusion called the primary cilium. Recent studies in mice and humans have highlighted the importance of the primary cilium in disease states affecting the limb, kidney, skeleton, brain, eyes, ears and lungs, as well as obesity and diabetes. We have isolated a novel mouse with a defect in the machinery required for correct functioning of the primary cilium. This mouse has widespread abnormalities and will be used to elucidate the role of cilia in disease.
Control Of Blood Vessel Development By SOX Transcription Factors
Funder
National Health and Medical Research Council
Funding Amount
$495,750.00
Summary
Cardiovascular disease is Australia s greatest health problem, with an estimated 3 million Australians suffering a spectrum of conditions from hypertension through to heart failure. Improper development of blood vessels in the embryo can compromise survival of the embryo, and predispose patients to vascular disease after birth. The growth of new blood vessels (angiogenesis) is also an important factor in the ability of solid tumours to grow during the progression of cancer. It is therefore of fu ....Cardiovascular disease is Australia s greatest health problem, with an estimated 3 million Australians suffering a spectrum of conditions from hypertension through to heart failure. Improper development of blood vessels in the embryo can compromise survival of the embryo, and predispose patients to vascular disease after birth. The growth of new blood vessels (angiogenesis) is also an important factor in the ability of solid tumours to grow during the progression of cancer. It is therefore of fundamental importance in the health sciences to gain an understanding of how blood vessels form and regenerate. We discovered a gene, Sox18, that appears to regulate blood vessel development by controlling the formation and-or properties of endothelial cells, which line the blood vessels and make them impermeable. Our research so far indicates that MICE WITH DEFECTS IN SOX18 DIE FROM VASCULAR DEFECTS, underlining the importance of this gene. THIS PROJECT IS CONCERNED WITH FINDING OUT HOW SOX18 WORKS - exactly what goes wrong in mice lacking this gene, whether Sox18 can influence endothelial cell behaviour in cell culture, how Sox18 comes to be active in endothelial cells, what genes are switched on by Sox18, and what genes Sox18 co-operates with in its role in endothelial cells. The answers to these questions will not only provide fundamental basic information about how blood vessels development is controlled, but also sow the seeds for possible future therapies in which blood vessel development could be stimulated (eg in wound healing) or suppressed (eg in tumour progression) by drug treatments.Read moreRead less
Defining The Genetic Causes Of The Abnormal Vertebral Segmentation Syndrome, Spondylocostal Dysostosis
Funder
National Health and Medical Research Council
Funding Amount
$476,523.00
Summary
There are many birth defects that cause vertebral malformations along the spinal column. These occur as the embryo develops in utero, during the formation of structures known as somites. Somites also form the ribs, muscle, tendons and dermis. We are studying an example of this type of birth defect called spondylocostal dysostosis (SCD). We have shown that mutations in three different genes cause some cases of this inherited disease in humans. These genes are called DLL3, MESP2 and LFNG. However, ....There are many birth defects that cause vertebral malformations along the spinal column. These occur as the embryo develops in utero, during the formation of structures known as somites. Somites also form the ribs, muscle, tendons and dermis. We are studying an example of this type of birth defect called spondylocostal dysostosis (SCD). We have shown that mutations in three different genes cause some cases of this inherited disease in humans. These genes are called DLL3, MESP2 and LFNG. However, 80% of SCD patients do not have a mutation in any of these genes. Thus we need to discover how these other cases occur. This project uses two strategies in parallel. Firstly, we will analyse large families that have a history of SCD, and use this information to find causative gene mutations. However, a significant proportion of cases occur without family history. To find out what genes are involved in these cases is more difficult. We have created a mutant mouse by specifically deleting the DLL3 gene. This mouse has very similar vertebral malformations to SCD. We will compare embryos from normal and mutant mice to find genes that do not operate normally in the mutant. These genes are candidates for causing SCD, and thus we will screen these genes in human patients for mutations. However, simply finding a change in a candidate gene does not necessarily mean that this is the cause of SCD. To prove this, we have developed several tests to determine if the mutation alters the normal function of the protein encoded by the mutated gene. This work will greatly benefit the future genetic assessment of SCD patients. In addition, by studying our mouse model of SCD, we will gain a greater understanding of how DLL3 functions. This knowledge may be useful in developing stem cell-based therapies that involve the production of specific cell types.Read moreRead less
Defining The Genetic And Environmental Factors That Cause Abnormal Vertebral Segmentation During Embryogenesis
Funder
National Health and Medical Research Council
Funding Amount
$724,147.00
Summary
Many birth defects cause vertebral malformations along the spinal column. They originate as the fetus forms, and may be caused by gene mutation or environmental factors. Whilst studying one type of vertebral malformation we have found a genetic cause for 30% of cases. We will investigate the genetic and environmental cause of the remainder. We will look for new genes causing this disease, and use a mouse model to learn how low oxygen levels during pregnancy causes such malformations
The Role Of The Mammalian Grainyhead-like Gene Family In Neural Tube Closure
Funder
National Health and Medical Research Council
Funding Amount
$635,547.00
Summary
Failure of the skin to close over the brain and spinal cord during human development results in the devastating congenital birth defects anencephaly and spina bifida, known collectively as the neural tube defects. These are the second most common congenital birth defects affecting 1:1000 pregnancies. Our laboratories have identified a family of genes essential for the closure of the neural tube in mammals. The aim of this proposal is to understand the mechanisms of action of these genes with a v ....Failure of the skin to close over the brain and spinal cord during human development results in the devastating congenital birth defects anencephaly and spina bifida, known collectively as the neural tube defects. These are the second most common congenital birth defects affecting 1:1000 pregnancies. Our laboratories have identified a family of genes essential for the closure of the neural tube in mammals. The aim of this proposal is to understand the mechanisms of action of these genes with a view to developing new preventative therapeutics.Read moreRead less
Hedgehog Signalling In Limb And Craniofacial Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$494,544.00
Summary
Anomalies of the face and limbs are amongst the most common features of human birth defects, and their frequent association suggests that the same genes are involved in governing the development of the limbs and face during embryogenesis. We have used a genomics-based approach to identify genes involved in limb development based on their alteration in a mouse model which develops extra fingers and toes. Defects in this mouse result from changes in Gli3, a gene which is known to be important in b ....Anomalies of the face and limbs are amongst the most common features of human birth defects, and their frequent association suggests that the same genes are involved in governing the development of the limbs and face during embryogenesis. We have used a genomics-based approach to identify genes involved in limb development based on their alteration in a mouse model which develops extra fingers and toes. Defects in this mouse result from changes in Gli3, a gene which is known to be important in both limb and face development. Based on the organs in which our genes of interest are active, we believe that they will also play key roles in embryonic development of the limbs, face and other organs. We now plan to investigate the regulation of a subset of these genes based on analysis in mouse models of limb and face development. In addition, we have chosen to further analyse the function of a completely novel gene we have identified which our preliminary studies suggest may play a role in the normal development of the lip and palate. These studies have the potential to shed light on the processes governing how organs develop, as well as on the molecular basis of common birth defects such as polydactyly (extra fingers and toes) and cleft palate.Read moreRead less
Functional Characterization Of Caveolae And Caveolins
Funder
National Health and Medical Research Council
Funding Amount
$140,660.00
Summary
This project aims to study the cellular machinery that allows a cell to respond to its external environment. Specifically, this project focusses on the function of a family of membrane proteins, called caveolins, which are the major protein components of caveolae small pits which cover the surface of many mammalian cells. Caveolins are believed to regulate signalling from the external environment to the cell interior and loss of this regulation leads to uncontrolled growth leading to cancer. Sig ....This project aims to study the cellular machinery that allows a cell to respond to its external environment. Specifically, this project focusses on the function of a family of membrane proteins, called caveolins, which are the major protein components of caveolae small pits which cover the surface of many mammalian cells. Caveolins are believed to regulate signalling from the external environment to the cell interior and loss of this regulation leads to uncontrolled growth leading to cancer. Signalling from the cell surface relies on organisation of signalling components into modules. Our studies suggest that these modules are dependent on specific lipid molecules which form discrete patches, called lipid rafts, on the cell surface. We have hypothesised that caveolins control the lipid molecules associated with lipid rafts and so, indirectly, control signalling pathways. In particular, we have shown that caveolin is important in the regulation of cellular cholesterol, a vital molecule involved in maintaining the function of lipid raft domains. As numerous human diseases are associated with cholesterol imbalance, studies of caveolins can give fundamental new insights into this process, and the previously unidentified links between the cellular lipid balance and signal transduction. This project aims to use mutant caveolin molecules to disrupt caveolin function and so determine the role of caveolin in lipid regulation and in signal transduction. We will then use a lower vertebrate model system, which is amenable to experimental manipulation, to determine the role of caveolins and rafts in the development of the whole embryo.Read moreRead less
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
Understanding How Placental Development Is Affected By Cellular Hypoxia And Cited2, A Hypoxia-responsive Gene.
Funder
National Health and Medical Research Council
Funding Amount
$352,500.00
Summary
During pregnancy the mammalian fetus depends entirely on its mother for nutrition and oxygen, and to remove waste products. These are exchanged in the placenta, where the blood supplies of the mother and fetus come into close proximity. The placenta is connected to the mother via blood vessels in the uteruine wall, and to the fetus via the umbilical cord. This organ is also involved in making hormones necessary for mammary gland development, suppression of the local immune system to prevent feta ....During pregnancy the mammalian fetus depends entirely on its mother for nutrition and oxygen, and to remove waste products. These are exchanged in the placenta, where the blood supplies of the mother and fetus come into close proximity. The placenta is connected to the mother via blood vessels in the uteruine wall, and to the fetus via the umbilical cord. This organ is also involved in making hormones necessary for mammary gland development, suppression of the local immune system to prevent fetal rejection, and production of progesterone required to maintain the pregnancy. Thus failure of correct placenta formation can be associated with a range of complications of human pregnancy, such as missed abortion, miscarriage, intrauterine growth restriction, and pre-eclampsia. The exact cause of these complications is unknown, but by studying mouse models with placental defects we hope to address these issues. Many of the common diseases in society, such as heart attack, stroke and pre-eclampsia, are either directly or indirectly the result of an organ being deprived of oxygen (termed hypoxia). Mammals respond to hypoxia in several different ways to deliver more oxygen to the affected area, such as increasing numbers of oxygen-carrying red blood cells, enlarging existing blood vessels, and making new vessels. Many of the genes involved in this process are known, and one of these is called Cited2. Paradoxically, during gestation hypoxia is crucial for the normal formation of many fetal organs and their blood supply, including the placenta. We have created a mutant mouse by specifically deleting the Cited2 gene. Mutant mouse embryos die during gestation and do not form a fully functional placenta. We will examine these defective placentas in order to understand how this organ needs Cited2 to form. Since the Cited2 gene is turned on by hypoxia, this will also allow us to see if the placental defects are caused by a failure of the normal response to hypoxia.Read moreRead less