Transcriptional Control Of Blood Vessel Development By Sox18
Funder
National Health and Medical Research Council
Funding Amount
$468,564.00
Summary
Blood vessels play an essential role in maintaining the supply of nutrients to every organ and tissue in the body. Improper development of blood vessels in the embryo can compromise survival of the embryo, and defects in the ability of blood vessels to grow, regenerate and adapt to change during adult life can be life-threatening. 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 ....Blood vessels play an essential role in maintaining the supply of nutrients to every organ and tissue in the body. Improper development of blood vessels in the embryo can compromise survival of the embryo, and defects in the ability of blood vessels to grow, regenerate and adapt to change during adult life can be life-threatening. 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. As a result of our collaborative research efforts, we have discovered a gene, Sox18, that appears to regulate blood vessel development by controlling the formation and-or behaviour 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) through pharmaceutical intervention.Read moreRead less
The Role Of Sox8 In Sex Determination And Human Disease
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
We have discovered a new gene called Sox8. This gene is very closely related to another gene, Sox9, that is known to be a critical factor in determining whether an embryo develops as a male or female by specifying whether the embryo makes testes or ovaries. We have found that Sox8, like Sox9, is active in the cell type in fetal testes known to be important for the development of maleness, at around the time when the male-female decision is being made. We therefore believe that Sox8 is an importa ....We have discovered a new gene called Sox8. This gene is very closely related to another gene, Sox9, that is known to be a critical factor in determining whether an embryo develops as a male or female by specifying whether the embryo makes testes or ovaries. We have found that Sox8, like Sox9, is active in the cell type in fetal testes known to be important for the development of maleness, at around the time when the male-female decision is being made. We therefore believe that Sox8 is an important part of the genetic chain of events leading to normal male development. We aim to study how Sox8 exerts its effects on male development. We have also found that in humans, Sox8 is located in a chromosomal region associated with a developmental disease syndrome characterized by mental retardation, facial defects and anomalies of male sexual development. Sox8 is active in mouse embryos in all the tissues affected by the human disease. We believe defects in SOX8 in humans are largely responsible for this disease, called ATR-16 syndrome. We will test whether patients with ATR-16 have defects involving SOX8 in their DNA in order to test this theory. In summary, we believe we have found a new human disease gene which will further our understanding of how developmental diseases arise in the embryo. In addition, this work will shed light on the process of sexual development, a significant healthcare problem in view of the fact that defects in sexual development are among the most common forms of birth defects.Read moreRead less
The Role Of SOX14 In Limb Development And Human Limb Defects.
Funder
National Health and Medical Research Council
Funding Amount
$257,606.00
Summary
Little is known about the mechanisms that control limb development. We have discovered a new gene which is active in the developing limb of the embryo. This study will provide information on how this new gene controls the development of the limb. Limb defects occur in 1 in 1,000 new-born babies. We believe the absence of our newly discovered gene may be responsible for some of these limb defects. Ultimately, this fundamental knowledge may lead to improved pre-natal diagnosis and better treament ....Little is known about the mechanisms that control limb development. We have discovered a new gene which is active in the developing limb of the embryo. This study will provide information on how this new gene controls the development of the limb. Limb defects occur in 1 in 1,000 new-born babies. We believe the absence of our newly discovered gene may be responsible for some of these limb defects. Ultimately, this fundamental knowledge may lead to improved pre-natal diagnosis and better treament for limb abnormalities.Read moreRead less
Role Of Human SRY And SOX9 In Sex Determination And Disease.
Funder
National Health and Medical Research Council
Funding Amount
$308,820.00
Summary
The decision to develop as a male or female is controlled by a genetic pathway which culminates in the development of a testis or an ovary in the human embryo. The correct development of these reproductive organs depends on the coordinated activation of a network of genes by transcription factors. Analysis of patients with defective reproductive organs has shown that a number of these individuals have mutations in two transcription factor genes, SRY and SOX9. Mutations in SRY (Swyer syndrome) or ....The decision to develop as a male or female is controlled by a genetic pathway which culminates in the development of a testis or an ovary in the human embryo. The correct development of these reproductive organs depends on the coordinated activation of a network of genes by transcription factors. Analysis of patients with defective reproductive organs has shown that a number of these individuals have mutations in two transcription factor genes, SRY and SOX9. Mutations in SRY (Swyer syndrome) or SOX9 (autosomal sex reversal-campomelic dysplasia) cause the development of female reproductive structures in individuals with male chromosomes. Towards understanding how SRY and SOX9 work to determine sex, we have identified four proteins that interact with SRY and SOX9. Two of these proteins, called importin-beta and calmodulin have a role in transporting SRY and SOX9 into the cell nucleus. The other two proteins, called PC4 and HSP70, appear to be involved in co-operating with SRY and-or SOX9 to turn genes on. In the developing mouse testis, a large number of genes are expressed at the time immediately following the expression of SRY and SOX9. We will identify which of these 50 genes are being directly switched on or off by SRY and SOX9 during sex determination. These studies will identify how SRY and SOX9 direct normal testis formation and how mutations cause developmental defects. Also, by unravelling the testis formation pathway, we expect to identify new genes involved in sexual dysmorphology syndromes.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
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
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
Functional Analysis Of Candidate Sex-determining And Gonadal Development Genes
Funder
National Health and Medical Research Council
Funding Amount
$503,500.00
Summary
This project is aimed at finding and studying the genes that control whether an embryo develops as a male or a female, and the genes that are responsible for proper development of the gonads, organs that control an individual's sexual development. It is thought that a genetic chain of events is important for gonadal development, and we aim to find the missing links of that chain and to work out how they fit together, as well as how genetic defects can lead to disorders of sexual development. Def ....This project is aimed at finding and studying the genes that control whether an embryo develops as a male or a female, and the genes that are responsible for proper development of the gonads, organs that control an individual's sexual development. It is thought that a genetic chain of events is important for gonadal development, and we aim to find the missing links of that chain and to work out how they fit together, as well as how genetic defects can lead to disorders of sexual development. Defects in sexual development in the human embryo not only result in some of the most common forms of birth defects but also have profound physiological and psychosexual ramifications for the afflicted individuals. A fuller understanding of the causes of these defects will lead to improved patient management.Read moreRead less
Role Of The T-box Transcription Factors, Tbx5 And Tbx20, In Cardiac Development And Congenital Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$345,000.00
Summary
Structural defects in the heart are present in approximately 1 in 100 live births, and 1 in 10 still births in developed countries. Some 8% of deaths in the first year of life are caused by such abnormalities. While some defects can be repaired in childhood many go undetected and compound in later years leading to sudden death or compromised quality of life. Virtually all inherited heart defects for which the underlying genetic alteration is known are caused by mutations in genes controlling dev ....Structural defects in the heart are present in approximately 1 in 100 live births, and 1 in 10 still births in developed countries. Some 8% of deaths in the first year of life are caused by such abnormalities. While some defects can be repaired in childhood many go undetected and compound in later years leading to sudden death or compromised quality of life. Virtually all inherited heart defects for which the underlying genetic alteration is known are caused by mutations in genes controlling development of the heart in the embryo. Examples are Tbx5, a member of the T-box family of transcription factor genes mutated in Holt Oram syndrome, and Nkx2-5, a homeodomain transcription factor gene mutated in families with hole in the heart and cardiac electrical defects. We propose to investigate the involvement of a new member of the T-box gene family, Tbx20, in cardiac development and disease, and to compare and contrast its function with that of Tbx5. The Tbx5 and Tbx20 proteins interact directly with Nkx2-5 to stimulate transcription of cardiac genes, making Tbx20 a good candidate for involvement in inherited disease. We will use gene targeting technology to delete the Tbx20 gene in mice, and will analyse heart anatomy, gene expression and function to determine the effect of its loss. We will also investigate how Tbx20 interacts with other cardiac regulatory pathways, by crossing Tbx20 mutant mice with mice deficient for Nkx2-5 and Tbx5, strains that show heart abnormalities similar to those found in human patients. Microarray technology, which examines gene expression on a whole genome scale, will also be used to identify genes that are regulated by these transcription factors. Finally, we will search for mutations in the Tbx20 gene in human patients that have inherited heart abnormalities. In doing so we may improve our understanding of disease causation and predisposition thereby identifying patients at risk and providing improved genetic counselling and diagnosis.Read moreRead less
Defects in sexual development in the human embryo result in some of the most common forms of birth defects, which have profound physiological and psychosexual ramifications for the afflicted individuals. A fuller understanding of the causes of these defects may lead to improved counseling and perhaps also therapeutic possibilities. This project is aimed at finding and studying the genes that control whether an embryo develops as a male or a female, and the genes that are responsible for proper d ....Defects in sexual development in the human embryo result in some of the most common forms of birth defects, which have profound physiological and psychosexual ramifications for the afflicted individuals. A fuller understanding of the causes of these defects may lead to improved counseling and perhaps also therapeutic possibilities. This project is aimed at finding and studying the genes that control whether an embryo develops as a male or a female, and the genes that are responsible for proper development of the gonads, organs that control an individual's sexual development. It is thought that a genetic chain of events is important for gonadal development, and we aim to find the missing links of that chain and to work out how they fit together.Read moreRead less