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
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
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 HuB RNA-binding Protein In Post-transcriptional Gene Regulation In The Pre-gastrula Zebrafish Embryo
Funder
National Health and Medical Research Council
Funding Amount
$545,216.00
Summary
The precise control of protein expression is absolutely critical in biology. The key decisions about which genes are turned on or off at any one moment control the proper growth of an organism during development, and are responsible for the organism's homeostasis and proper response to environmental changes as an adult. The spatio-temporal control of genes is critcal during embryogenesis and we aim to understand how these processes underlie development in the vertebrate embryo.
One of the most critical steps in embryonic development is the assembly of the different tissue components into a three-dimensional structure in order to build a major body part of the foetus. In the development of the head, this form-shaping process undertaken by different cell populations is coordinated by genetic activity that is triggered by signals received by cells. The objective of our research is to understand how one of the many signalling mechanisms, WNT signalling, works in making the ....One of the most critical steps in embryonic development is the assembly of the different tissue components into a three-dimensional structure in order to build a major body part of the foetus. In the development of the head, this form-shaping process undertaken by different cell populations is coordinated by genetic activity that is triggered by signals received by cells. The objective of our research is to understand how one of the many signalling mechanisms, WNT signalling, works in making the head and face of the embryo. We will study the development of embryos of mice in which mutations have been introduced experimentally in genes that code for factors of the WNT signalling pathway. Understanding the complexity of tissue interactions and the interplay of molecular mechanisms of head formation in the embryo is a major challenge. However, knowledge of the processes in animal models will contribute to a better delineation of the role of signalling in normal head development. It will also help to direct the focus of future clinical investigations to the most relevant genetic determinants of birth defects of the head and face, which is present in about 8 per 10,000 births in Australia.Read moreRead less
Genetic Control Of Body Patterning: Intersection Of Transcriptional And Signalling Activity In Head Formation
Funder
National Health and Medical Research Council
Funding Amount
$579,932.00
Summary
A most critical step in embryonic development is the assembly of the different tissue components into a three-dimensional structure in order to build a major body part of the foetus. The objective of our research is to understand how the mechanisms that control genetic activity and cell-to-cell signalling may cooperate in the formation of the head and face of the embryo. The outcome will focus future clinical investigations to the most relevant genetic determinants of craniofacial defects.
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.
From Endoderm To Gut: Regulation Of Lineage Allocation And Morphogenesis In The Murine Embryo
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
One of the most critical steps in early development is the generation of the full complement of cell types required to build the embryo. A thorough understanding of the mechanisms underlying this is vital for the development of methods for directing the differentiation of stem cells for use in regenerative medicine. The objective of our research is to understand the cellular and molecular mechanisms underlying the assignment of cells to particular fates and the establishment of the body plan of ....One of the most critical steps in early development is the generation of the full complement of cell types required to build the embryo. A thorough understanding of the mechanisms underlying this is vital for the development of methods for directing the differentiation of stem cells for use in regenerative medicine. The objective of our research is to understand the cellular and molecular mechanisms underlying the assignment of cells to particular fates and the establishment of the body plan of the embryo. The endodermal cell layer forms the lining of the embryonic gut which gives rise to the entire gastrointestinal tract, the respiratory tract and other structures including the liver and the pancreas during organogenesis. This investigation focuses on the questions of how the pluripotent progenitor cells are allocated to the endodermal lineage and how the embryonic gut is patterned during early development of the mouse embryo. Analysis of endoderm development will provide insights into the roles of the allocation of progenitor cells to tissue lineages, cell movement, and diversification and maturation of functional cell types. These processes are universally relevant to the formation of all types of organ primordia in the embryo. Understanding the complexity of tissue interactions and the interplay of molecular mechanisms of cell lineage choice and differentiation in the embryo is a major challenge. However, knowledge of the processes that drive tissue differentiation in the embryo is absolutely crucial for enhancing our ability to direct cell and tissue differentiation for the realization of cell-based technologies in biomedicine.Read moreRead less