Regulation Of Pre-mRNA And MRNA Processing By The Neuron-specific Hu RNA-binding Proteins
Funder
National Health and Medical Research Council
Funding Amount
$477,750.00
Summary
The precise control of protein expression is absolutely critical in biology, and the key decisions about which genes are turned on or off at any one moment control the proper growth and maturation of an organism during development, and are responsible for the organism's homeostasis and proper response to environmental changes as an adult. Many gene expression programs are highly complex and controlled by regulating the activation of individual genes as they are copied from DNA to RNA. However, t ....The precise control of protein expression is absolutely critical in biology, and the key decisions about which genes are turned on or off at any one moment control the proper growth and maturation of an organism during development, and are responsible for the organism's homeostasis and proper response to environmental changes as an adult. Many gene expression programs are highly complex and controlled by regulating the activation of individual genes as they are copied from DNA to RNA. However, this activation is just the start of the process to produce an active protein. In higher organisms, these RNA copies almost always contain interruptions called introns, which must be excised from the RNA. Also, protein factors bound to specific RNAs can dictate whether the RNA is used to make protein or not, and these factors can also affect the localisation of the RNA to a specific sub-cellular destination, giving rise to highly localised protein expression. Evidence suggests that neurons are a cell type that rely heavily on mechanisms of RNA regulation. During development neurons become highly polarised, acquiring an axon which can elongate and find distant synaptic targets. While much is known about how axon growth cones respond to various guidance cues, the mechanisms by which the axon is able to translate this guidance cue information into structural changes which allow the growth cone to expand or collapse is largely unexplored. Recent evidence suggests that accurate growth cone guidance is absolutely dependent upon local protein synthesis. The functional corollary of this finding is that axon guidance requires RNA localisation and control of protein synthesis of RNAs in the growth cone. This phenomenon of spatial gene regulation within an individual cell is a central research interest for understanding how the brain functions.Read moreRead less
Identification Of Genes For X-linked Mental Retardation.
Funder
National Health and Medical Research Council
Funding Amount
$675,228.00
Summary
We propose to identify novel heritable causes of intellectual disability using 22 large and well-characterised families from Australia. In these families we have refined the location of the genetic defect to the chromosome X and excluded the contribution of all so far known genes. We will achieve this using the technology of massive parallel sequencing. At the completion of the project we will have identified novel causes of intellectual disability and devised tests to identify them.
Common Fragile Site Genes: Function And Contribution To Cancer Cell Biology
Funder
National Health and Medical Research Council
Funding Amount
$474,597.00
Summary
Common fragile sites are regions on human chromosomes that everybody has. These regions are much more sensitive to damage from agents in the environment (including the diet) than other regions in human chromosomes - so when damage does occur it is more likely to occur at these fragile sites. Many of the most sensitive fragile sites have large genes that span them. We need to understand the function of these genes to see how their disruption can contribute to cancer.
The Role Of The Gtf2i Gene Family In Behaviour And Williams Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$629,396.00
Summary
Williams Syndrome (WS) is a complex neurodevelopmental disorder in humans caused by a deletion of 21 genes on chromosome 7. This results in a reduced IQ and marked visuospatial deficiencies. However, unlike other forms of mental retardation, some important cognitive abilities are completely normal. WS patients show normal development of linguistic abilities and anecdotal evidence suggests they possess an above average musical ability. In addition, these individuals also possess a characteristic ....Williams Syndrome (WS) is a complex neurodevelopmental disorder in humans caused by a deletion of 21 genes on chromosome 7. This results in a reduced IQ and marked visuospatial deficiencies. However, unlike other forms of mental retardation, some important cognitive abilities are completely normal. WS patients show normal development of linguistic abilities and anecdotal evidence suggests they possess an above average musical ability. In addition, these individuals also possess a characteristic overfriendly, gregarious personality with little inhibition towards strangers. Such a characteristic cognitive and behavioral profile in a genetic disorder has provided convincing evidence that genes play a role in specifying cognitive abilities and behavior. This interesting syndrome gives us an insight into the perplexing debate of Nature vs Nurture. It also provides a unique and invaluable opportunity to dissect the role of certain genes in complex neurodevelopmental pathways that result in cognition and behavior. Recently, patients with smaller (atypical) deletions of genes in the WS region have been described. These patients do not display the full 'classical' range of WS characteristics. The identification of which genes are deleted in these patients suggests that two genes in particular, GTF2IRD1 and GTF2I, are involved in visuospatial abilities, sociability and specific anxieties and phobias. Our laboratory was the first to identify proteins encoded by GTF2IRD1, known as MusTRDs, that act for the most part to suppress gene expression. Furthermore, our laboratory has been studying a mouse model in which the Gtf2ird1 gene has been deleted, similar to the situation in WS, and have found that the mice are more 'social' and exploratory. In this project, we want to determine if other behavioural features of WS are contributed to by this gene and-or its related gene, Gtf2i, and to characterize the role that these genes play in neuronal cell function.Read moreRead less
A Structural And Functional Basis For The Regulation Of Gene Expression By Nuclear Retention Of RNA
Funder
National Health and Medical Research Council
Funding Amount
$504,097.00
Summary
The nuclear retention mechanism is a novel way used by cells to control which genes are made into proteins - a fundamental process for all diseases, particularly cancers. This project will employ cutting edge structural and proteomic techniques to determine the molecular details underpinning nuclear retention. These insights will be important for the development of new tissue-restricted gene therapy applications and drugs targeting the cancers that rely on this mechanism.