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The Role Of The Suppressors Of Cytokine Signalling 6 And 7 In Cerebral Cortex Development
Funder
National Health and Medical Research Council
Funding Amount
$377,189.00
Summary
Defects in neuronal cell migration during embryonic development lead to mental retardation and epilepsy. Although neuronal migration is essential for the development of normal intelligence, we know relatively little about the molecular mechanisms that regulate this process. We have identified two proteins, Socs6 and Socs7, which are essential for neuronal migration and normal cerebral cortex development. We propose to fully investigate the function of Socs6 and Socs7 during cortex development.
The Role Of Rnd Genes During Cortical Neurogenesis And Cell Migration
Funder
National Health and Medical Research Council
Funding Amount
$410,384.00
Summary
In order for the brain to function properly, tens of billions of neurons within it first have to be born, then find their proper location before connecting with other neurons in a highly ordered fashion. Failure of these key processes heavily impacts on subsequent brain function, and have been shown to underlie several disorders including epilepsy. This study will investigate how members of the Rnd gene family control cell production and positioning within the developing brain.
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
Mechanisms Controlling Interneuron Migration And Layering In The Cortex
Funder
National Health and Medical Research Council
Funding Amount
$613,060.00
Summary
This work will increase our understanding of how the brain is assembled and what mechanisms control this process. Understanding this highly orchestrated string of events is vital as abnormal positioning and numbers of neurons are known pathologies in brains of patients with epilepsy and schizophrenia. Using state of the art equipment we can visualize neurons moving in brain slices in real-time and investigate environmental factors involved in this important process.
The Role Of Reelin-signalling On Cortical Neuron Migration
Funder
National Health and Medical Research Council
Funding Amount
$716,196.00
Summary
Disorders that occur during brain development can lead to abnormal behaviours traits such as anxiety and altered social interactions, plus abnormalities in neuronal function and information processing. The region of the brain responsible for originating the motor, sensory and cognitive functions of a human is the cortex. This brain region is comprised of two major types of neurons that are arranged in a highly organized manner. One captivating aspect of the brain is that during early stages of d ....Disorders that occur during brain development can lead to abnormal behaviours traits such as anxiety and altered social interactions, plus abnormalities in neuronal function and information processing. The region of the brain responsible for originating the motor, sensory and cognitive functions of a human is the cortex. This brain region is comprised of two major types of neurons that are arranged in a highly organized manner. One captivating aspect of the brain is that during early stages of development neurons are generated in one part of the brain and migrate great distances to a final destination. It is therefore necessary during development to have a well-orchestrated, controlled series of events that lead to the correct positioning and association of neurons. The precise functions of many gene products involved in this process are not known. One major advancement in the development of the cortex is the discovery of the protein Reelin which is found in the outermost region of the developing cortex. Mutations in Reelin, in humans, have been implicated in the causation of schizophrenia and mood disorders. These disease states are the result of altered migration of neurons in the cortex. The research proposed in this application is designed to understand the precise process of how two types of neurons migrate and assemble in the cortex. Technology today allows us to visualize, in culture, neurons as they migrate in real-time. This is referred to real time-lapse imaging and allows the researcher the ability to examine how external factors, affect migration of cortical neurons. We will determine how Reelin is involved in this process and our research will elucidate the fundamental process of cortical brain development.Read moreRead less
THE ROLE OF UBIQUITIN LIGASE ADAPTOR PROTEIN NDFIP1 IN NEURONAL DEVELOPMENT
Funder
National Health and Medical Research Council
Funding Amount
$581,813.00
Summary
Many brain diseases are characterized by faulty connections between nerve cells (neurons), in some cases caused by the inability to remove unwanted proteins from the neuron. This function is carried out by the ubiquitin-proteasome system (UPS). We have evidence that a UPS protein called Ndfip1 is important for forming functional brain circuits. We aim to discover whether neuron growth, branching and connectivity is promoted by Ndfip1 targeting of PTEN (phosphatase with tensin homology) to the UP ....Many brain diseases are characterized by faulty connections between nerve cells (neurons), in some cases caused by the inability to remove unwanted proteins from the neuron. This function is carried out by the ubiquitin-proteasome system (UPS). We have evidence that a UPS protein called Ndfip1 is important for forming functional brain circuits. We aim to discover whether neuron growth, branching and connectivity is promoted by Ndfip1 targeting of PTEN (phosphatase with tensin homology) to the UPS.Read moreRead less
DCC-Robo Interactions Cooperate To Regulate Callosal Axon Guidance
Funder
National Health and Medical Research Council
Funding Amount
$383,422.00
Summary
In order for the brain to function, the correct connections between neurons must be formed during development. These connections, formed by the axonal processes of neurons, are able to find their synaptic targets by sensing molecular cues within the brain that guide them, by attraction or repulsion, to their target. This proposal investigates how attractive and repulsive signals are received and integrated in neurons to enable axons to find their targets in the brain.
Genetic Cues Responsible For Interneuron Migration And Layering In The Neocortex
Funder
National Health and Medical Research Council
Funding Amount
$650,250.00
Summary
Understanding how the brain is assembled, and the genes that drive this process, will provide insights into two exciting areas of current neuroscience. First, it will clarify how we differ from other species, and illuminate the evolutionary concepts underscoring functional specialization. Secondly, there are sound health-related reasons to study brain development. Proper brain function requires the proper assembly of neurons and the establishment of circuitry. Defective generation of neurons in ....Understanding how the brain is assembled, and the genes that drive this process, will provide insights into two exciting areas of current neuroscience. First, it will clarify how we differ from other species, and illuminate the evolutionary concepts underscoring functional specialization. Secondly, there are sound health-related reasons to study brain development. Proper brain function requires the proper assembly of neurons and the establishment of circuitry. Defective generation of neurons in sufficient numbers, or impediments to neuron migration to proper destinations are certain recipes for neurological disorders, including epilepsy and mental retardation. In this application, we will study how neurons are assembled in the cortex. We will focus on a subpopulation known as interneurons that are vital for toning down electrical discharges from excitatory neurons. We will investigate how these neurons are able to migrate long distances to settle into defined layers of the cortex. Mutant mice with deleted genes have a defect in this process and the aim of this project will be to study the precise mode of action for some of these genes.Read moreRead less
Mechanisms Guiding Pathfinding And Positioning Of Cortical Interneurons
Funder
National Health and Medical Research Council
Funding Amount
$621,606.00
Summary
Brain disorders place an economic and social burden on Australia and the personal costs of these illnesses are immeasurable. Several brain abnormalities are caused from the failure of neurons to position themselves in the correct location when the brain develops. Our study aims to discover how neurons move and what factors influence this process. It provides an understanding of normal brain development, as well as providing insight into what may go wrong in the formation of brain diseases.
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