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
Birth defects can have devastating consequences for individuals and their families, and improving our ability to diagnose and screen for these disorders has implications for treatment and reproductive options. We are using the mouse as a model to discover genes important in a new class of birth defects caused by dysfunction of a hair-like cellular projection known as the cilium.
Signalling And Transcriptional Activity For Craniofacial Morphogenesis In An Experimental Genetic Mouse Model
Funder
National Health and Medical Research Council
Funding Amount
$74,755.00
Summary
Abnormalities in craniofacial development affect 2-1000 births in Australia. The aim of this project is to identify genes crucial for the development of the head and face. In particular the project focuses on the Twist1 gene. TWIST1 plays a key role in craniofacial development and individuals lacking functional Twist1display facial anomalies such as craniosynostosis and cleft palate. Dissecting the function of Twist1 is essential to identifying new avenues for the prevention of these defects.
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.
Development Of The Commissural Plate And Its Role In Forebrain Commissure Development
Funder
National Health and Medical Research Council
Funding Amount
$529,565.00
Summary
During development, neurons in one hemisphere of the brain connect and communicate with neurons in the opposite hemisphere. Such neural connections between the two hemispheres are called commissures, which are large bundles of axons (neural-wires) that cross the midline of the brain. There are three commissures in the forebrain: the corpus callosum, the hippocampal commissure and the anterior commissure. This wiring of the brain is essential to its proper function. When these connections don't f ....During development, neurons in one hemisphere of the brain connect and communicate with neurons in the opposite hemisphere. Such neural connections between the two hemispheres are called commissures, which are large bundles of axons (neural-wires) that cross the midline of the brain. There are three commissures in the forebrain: the corpus callosum, the hippocampal commissure and the anterior commissure. This wiring of the brain is essential to its proper function. When these connections don't form, the brain cannot integrate and process information in fundamental ways. Over 50 different human congenital disorders are associated with the malformation of one or more of these forebrain commissures. This proposal investigates the hypothesis that a midline structure, called the commissural plate (CP), regulates the development of all forebrain commissures. The CP was first described anatomically at the turn of the 20th century in a number of different species, and in humans in 1968. However, since this time, no papers have been published on the CP. Experiments in this proposal will use modern neuroanatomical techniques, particularly magnetic resonance imaging, molecular and mouse mutagenesis techniques, and axon guidance assays, to study the CP. We will test the hypothesis that there is something fundamentally unique about the CP as the midline crossing point for all commissural axons. We generate mouse mutants that disrupt only dorsal CP formation and then determine whether the subsequent development of the dorsal commissures occurs. We also perform molecular expression, and imaging analyses on human foetal brains. Our goal is to provide an understanding of what developmental events are disrupted in human congential disorders resulting in midline brain malformations and agenesis of the forebrain commissures. Understanding the basis of these disorders will lead to more accurate diagnoses and potentially their prevention through genetic counseling.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
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
Professor Elizabeth Elliott AM is an international leader in rare disease research, as Director of the Australian Paediatric Surveillance Unit and investigator on The Lililwan project in Fitzroy Valley's remote Aboriginal communities, WA. This will establish prevalence of Fetal Alcohol Spectrum Disorders (FASD); diagnose and manage affected children and support their carers; and provide data to inform service needs for FASD and prevention policy for alcohol use pregnancy.