Research opportunities in neuromuscular disorders with mouse models

Summary

There are currently research opportunities in the following areas:

Supervisor(s)

Associate Professor William (Bill) Phillips, Dr Dario Protti, Dr Catherine Leamey

Research Location

Camperdown - School of Medical Sciences - Bosch Institute

Program Type

Masters/PHD

Synopsis

Role of the teneurin genes in development and function of the mammalian neuromuscular junction (Masters only)
The teneurins (Ten-Ms) are cell-surface adhesion/signalling proteins. The work of Drs Leamey and Sawatari is helping to reveal how Ten-M proteins guide visual system axons to their correct targets in the developing brain. It has recently been reported that the homologous genes in the fruit fly Drosophila play a role in the development of the neuromuscular junction (NMJ; Mosca et al. 2012 Nature 484, 237-241). The overall aim of this collaborative project is to determine whether the mammalian teneurin genes also play a role in the development and function of the neuromuscular junction. This has the potential to open up a whole new avenue of research into the molecular pathways that guide the development of our neuromuscular connections. There are two separate but related projects:
1) Does knock-out of teneurin genes alter the structure of the developing mouse NMJ and/or motor behavior? This project will involve behavioral observations and confocal microscopy of NMJs. It will be supervised primarilly by Bill Phillips in collaboration with the other supervisors.2) Does knockout of teneurin genes alter neuromuscular transmission and short-term synaptic plasticity? This project will involve intracellular electrical recordings of synaptic potentials from muscle fibres. It will be supervised primarily by Dario Protti in collaboration with the other supervisors.

The L25 transgenic mouse, a new mouse model of motor neuron disease?
Motor neuron disease (MND) is a fatal neurodegenerative disease involving the loss of nerve-muscle connections, motor neurons and motor pathways. Several genes have so far been identified as causes of the inherited form of MND in a minority of patients but the full range of causes remain to be determined. Animal models of MND in which to study the disease mechanism and potential therapies are at currently inadequate. This project will characterize a mouse mutant line called L25 (created serendipitously by Frank Lovicu's team as a result of random insertion of a transgene). L25 mice display motor behaviour and premature death suggestive of motor neuron disease. We suspect that the insertion of the transgene may have disrupted an endogenous gene that is needed to sustain motor pathways in adult mice. The primary aims of the project are to define the motor phenotype and use microscopy to find out if there is degeneration of the descending upper motor neurons and/or spinal motor neurons and their neuromuscular connections in voluntary muscles. In parallel we will investigate which gene might be responsible by sequencing the transgene insertion site. If extended to a PhD we will also investigate the cell biology of the gene to begin to understand how it gives rise to the motor symptoms and screen patient DNA to see if mutation of the human equivalent gene is a cause of MND.

Additional Information

The L25 transgenic mouse, a new mouse model of motor neuron disease?
This project is a collaboration between Drs Phillips and Lovicu at the University of Sydney central campus and molecular geneticist, Dr Ian Blair and neurologist, Dr Stephen Reddel at Concord Hospital and the ANZAC Research Institute.

Keywords

Neuromuscular, Motor control, neurodegenerative diseases, Electrophysiology, confocal microscopy, immunofluorescence, transgenic mice, motor neuron, skeletal muscle, nervous system development, motor neuron disease, amyotrophic lateral sclerosis, Genetic disorders, brain histopathology, CNS histology

Opportunity ID

The opportunity ID for this research opportunity is: 672

Other opportunities with Associate Professor William (Bill) Phillips

• Molecular changes underlying maturation and adaptation of the neuromuscular synapse.
• Regulation of postsynaptic acetylcholine receptor clustering by neural agrin

Other opportunities with Dr Dario Protti

• Vision laboratory

Other opportunities with Dr Catherine Leamey

• Mechanisms of brain development