The Role Of The Ras Signalling Molecule, C3G, In The Interaction Of Neural Precursor Cells And Their Environment
Funder
National Health and Medical Research Council
Funding Amount
$319,446.00
Summary
Developmental brain disorders affect 1-3% of the population. The mental retardation disease spectrum includes neuronal migration disorders and neural precursor proliferation disorders. We propose to study a molecular mechanism regulating neuronal migration, survival and proliferation. We have identified a protein, C3G, which is essential for three aspects of nervous system development: (A) C3G limits neural precursor cell proliferation. (B) C3G is essential for neuronal survival. (C) C3G is cruc ....Developmental brain disorders affect 1-3% of the population. The mental retardation disease spectrum includes neuronal migration disorders and neural precursor proliferation disorders. We propose to study a molecular mechanism regulating neuronal migration, survival and proliferation. We have identified a protein, C3G, which is essential for three aspects of nervous system development: (A) C3G limits neural precursor cell proliferation. (B) C3G is essential for neuronal survival. (C) C3G is crucial for neuronal migration. C3G acts in a cascade of proteins, known as the Ras signalling pathway, which transmits signals from the extracellular environment into the cell nucleus to elicit appropriate responses of the cell to cues from the outside. We will identify proteins that, together with C3G, affect the important processes of neural precursor proliferation, and neuron survival and migration. This project will fully characterise a key regulatory mechanism of cellular processes crucial to the development of normal intelligence.Read moreRead less
Decoding Conserved Mechanisms That Control Neuronal Migration
Funder
National Health and Medical Research Council
Funding Amount
$526,950.00
Summary
During brain development, nerve cells interact with each other and their surrounding environment through a forest of molecules that are essential for precise cellular communication. Deficient signaling between these molecules causes defects in development and leads to disease. By employing genetic and biochemical approaches we propose to identify new mechanisms through which the brain develops, to better understand how brain diseases such as epilepsy and schizophrenia occur.
Sialyltransferase In The Bipolar And Schizophrenic Brain: Examining The Role Of A Novel Generalised Susceptibility Gene
Funder
National Health and Medical Research Council
Funding Amount
$512,627.00
Summary
Bipolar disorder and schizophrenia are two major psychiatric conditions affecting over 800,000 Australians. We have identified a new gene which contributes to increased risk to developing both bipolar disorder and schizophrenia. We will investigate the function of this gene in normal brain development, and how this function is disrupted in individuals with bipolar disorder and schizophrenia. Understanding the biological cause will help us define better treatments for these severe mental illnesse ....Bipolar disorder and schizophrenia are two major psychiatric conditions affecting over 800,000 Australians. We have identified a new gene which contributes to increased risk to developing both bipolar disorder and schizophrenia. We will investigate the function of this gene in normal brain development, and how this function is disrupted in individuals with bipolar disorder and schizophrenia. Understanding the biological cause will help us define better treatments for these severe mental illnesses.Read moreRead less
In Vivo Analysis Of The Molecular And Neural Mechanism That Underly An Association Of MiRNAs With Mental Disorders
Funder
National Health and Medical Research Council
Funding Amount
$593,778.00
Summary
Genetic studies on autism, schizophrenia, bipolar disorder and major depression suggest that these disorders affect the formation and maintenance of connections between neurons. A group of brain-specific microRNAs, which are regulatory molecules, are predicted to regulate connectivity. Levels of these molecules are found to be abnormal in brains of patients with schizophrenia. This proposal aims to elucidate the function of these microRNAs in the number of neuronal connections, and early motor b ....Genetic studies on autism, schizophrenia, bipolar disorder and major depression suggest that these disorders affect the formation and maintenance of connections between neurons. A group of brain-specific microRNAs, which are regulatory molecules, are predicted to regulate connectivity. Levels of these molecules are found to be abnormal in brains of patients with schizophrenia. This proposal aims to elucidate the function of these microRNAs in the number of neuronal connections, and early motor behavior in transgenic zebrafish.Read moreRead less
The Molecular Basis For Target Selection In The Central Nervous System By Sensory Axons
Funder
National Health and Medical Research Council
Funding Amount
$251,325.00
Summary
The normal function of the brain depends upon the specific connections that nerve cells make with each other. These connections are set up in the developing embryo when nerve cells send out long processes - axons - which grow towards their synaptic targets. How axons select their correct targets from amongst the millions of alternatives in the developing brain is unknown. A better understanding of this problem will help us develop therapies to assist regenerating axons re-establish correct conne ....The normal function of the brain depends upon the specific connections that nerve cells make with each other. These connections are set up in the developing embryo when nerve cells send out long processes - axons - which grow towards their synaptic targets. How axons select their correct targets from amongst the millions of alternatives in the developing brain is unknown. A better understanding of this problem will help us develop therapies to assist regenerating axons re-establish correct connections following injury to the brain or spinal cord. We propose to use a simple model system, the embryo of the fruitfly Drosophila, to find molecules that are involved in this process of neuron target recognition - ' axon targeting' molecules - and to study how they work. Drosophila can be genetically manipulated in ways not possible in higher animals. Furthermore the simplicity of its nervous system means that we can determine the connections of individual nerve cells with a high degree of precision. In the first part of our project, we will examine Drosophila embryos that carry mutations in genes suspected to code for targeting molecules. We will stain individual sensory nerve cells in these embryos with dyes to reveal the anatomy of their axons in the brain. If sensory axons terminate abnormally in the brain of a given mutant, the affected gene is likely to code for an axon targeting molecule. In the second part of the study, we will investigate the functions of candidate axon targeting molecules using two approaches. Firstly, we will seek to determine whether the molecule acts in the sensory axons or in their target cells. Secondly, we will use time-lapse microscopy to study how the homing behaviour of the sensory axons is affected in mutant embryos. The results of these studies will lead us closer to an answer to the question: How do axons recognise their specific target cells in the brain?Read moreRead less
The Role Of Cell Adhesion Molecules In Regulation Of Axon Advance
Funder
National Health and Medical Research Council
Funding Amount
$426,006.00
Summary
All cells contain on their surface a class of molecules, cell adhesion molecules, that enable them to adhere to other cells in tissues. Cell adhesion molecules have long been known to be involved in the guidance of axons to their targets during development. However the molecular mechanisms by which these molecules act are largely unknown. We propose to use the powerful genetic tools available in the fruitfly to dissect the mechanisms by which two cell adhesion molecules promote axon growth.
Investigating The Pathogenic Mechanism Of Mutations In IQSEC2 Causing Non-syndromic Intellectual Disability.
Funder
National Health and Medical Research Council
Funding Amount
$449,016.00
Summary
Intellectual disability is frequent in the population, as many as 1 in every 50 people in the world affected. Mutations in IQSEC2, an X-chromosome gene, cause intellectual disability. We will screen 1000 families with this disability for mutations in IQSEC2, building the picture of disease symptoms, contributing to informed genetic counselling. We will investigate functional impacts of these mutations in neuronal cultures, increasing our understanding of the causes of intellectual disability.
Role Of Chromatin Structure In The Regulation Of Stem Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$272,036.00
Summary
The aim of this project is to understand more about the nature of stem cells. Stem cells are cells which have the capacity to proliferate indefinitely but, at the same time, retain the capacity to differentiate into one or more cell types. Lower animals, such as amphibians, have a much greater capacity than humans to regenerate body parts. For example, axolotls can regenerate an entire limb if one limb is injured. This is because they retain undifferentiated stem cells in their limbs which can b ....The aim of this project is to understand more about the nature of stem cells. Stem cells are cells which have the capacity to proliferate indefinitely but, at the same time, retain the capacity to differentiate into one or more cell types. Lower animals, such as amphibians, have a much greater capacity than humans to regenerate body parts. For example, axolotls can regenerate an entire limb if one limb is injured. This is because they retain undifferentiated stem cells in their limbs which can be reactivated in the event of injury. Interestingly the adult human brain contains a small population of stem cells. The aim of this project is to find out more about how these cells remain undifferentiated and what is it about them which allows them to form different cell types. If more is known about these cells maybe in the future it will be possible to stimulate them to repair damaged parts of the nervous system. It may also be possible to treat people suffering from diseases like Alzheimer's disease, Parkinson's disease or spinal injuries.Read moreRead less
Neurons in the two hemispheres of the brain make connections with each other via a large fibre tract called the corpus callosum. In over fifty different human congenital syndromes the corpus callosum fails to form properly. Such syndromes, which include Aicardi syndrome, Andermann syndrome, Shapiro syndrome and Acrocallosal syndrome, can result in mental retardation, seizures, lack of motor coordination and ocular abnormalities in children. Our data on both mouse and human brain development show ....Neurons in the two hemispheres of the brain make connections with each other via a large fibre tract called the corpus callosum. In over fifty different human congenital syndromes the corpus callosum fails to form properly. Such syndromes, which include Aicardi syndrome, Andermann syndrome, Shapiro syndrome and Acrocallosal syndrome, can result in mental retardation, seizures, lack of motor coordination and ocular abnormalities in children. Our data on both mouse and human brain development show that the mouse is an excellent model system for understanding how the brain becomes wired up during development and what may go wrong in these disorders. Here we investigate the role of a family of genes called nuclear factor one (Nfi) genes in brain development. When mutated in mice, members of this gene family, principally Nfia and Nfib, cause severe malformations of the brain. The phenotype inlcudes a failure to form some midline glial populations, the expansion of the cingulate cortex and loss of the corpus callosum. The propoer formation of midline glial populations and the cingulate cortex are essential to callosal fomration and correct brain wiring. Defects in brain wiring in the cingulate cortex during development may underlie disorders such as schizophrenia, bipolar disorder and depression. In this project we will address the mechanism of function underlying the control of brain development by the Nfi genes. The expected outcomes of this research are to identify new mechanisms and genetic pathways critical to the formation of connections between the two sides of the brain and proper formation of the cingulate cortex. These results will improve our understanding of how the brain forms and what mechanisms may be disrupted during development that result in neurological and cognitive deficits in children and adults.Read moreRead less