Head Development: Genetic Determinants And Tissue Potency
Funder
National Health and Medical Research Council
Funding Amount
$947,116.00
Summary
Congenital malformations involving major defects of brain (anencephalus and related anomalies) and facial structures (ear, face and neck) are encountered in 3.4 and 1.4 per 10000 births respectively (Congenital Malformations Australia 1981-1996, National Perinatal Statistics Unit) and they constitute a substantial clinical burden. It is believed that these major structural defects usually result from abnormal development in the first trimester, which coincides with the time frame for the formati ....Congenital malformations involving major defects of brain (anencephalus and related anomalies) and facial structures (ear, face and neck) are encountered in 3.4 and 1.4 per 10000 births respectively (Congenital Malformations Australia 1981-1996, National Perinatal Statistics Unit) and they constitute a substantial clinical burden. It is believed that these major structural defects usually result from abnormal development in the first trimester, which coincides with the time frame for the formation of the basic components of the embryonic head in the mouse. Knowledge of the formation of the head in the mouse model is therefore relevant to the understanding of related developmental processes in early human development. This project which involves the application of sophisticated embryological and molecular analyses on mouse embryos generated by transgenesis and genetic manipulation provides a detailed studies of craniofacial morphogenesis in a mammalian model for early human development. The micro-manipulation procedures, embryo culture, fluorescence microscopy and the in situ hybridization are routinely performed in our laboratory, and most of the mouse lines are well established in my laboratory. Experiments proposed for this project that focus on the embryological and molecular analysis of normal and mutant embryos should discover new information on the cellular and molecular mechanisms that regulate head development. The knowledge will also offer insight into the pathogenesis of similar craniofacial malformations in other mutant embryos.Read moreRead less
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
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
Metabolic And Molecular Basis Of Embryo Signalling
Funder
National Health and Medical Research Council
Funding Amount
$409,836.00
Summary
Cells in the body are powered by mitochondria that essentially generate the energy required for development. This grant will determine how the environment affects the mitochondria in the developing embryo and determine the impacts to the embryo and pregnancy if a mitochondria is partially shut down.
It is clear that the health and disease burden of offspring can be programmed by events before birth. This project will answer questions as to how this programming occurs. My focus is to understand how the environment affects the oocyte, sperm and embryo and how this impacts on the offspring. We will specifically study the effects of obesity and nutritional status of the parents but also the in vitro environment with a view to improving IVF outcomes.