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== Signal transduction in the nervous system ==


We are interested in how the insulin and epidermal growth factor receptor (EGFR) signal transduction pathways control cell fate in the Drosophila nervous system. Both of these pathways are highly conserved and perform critical functions in both the developing and adult CNS. Aberrant activity of insulin or EGFR signalling can lead to disease and so understanding how these two pathways act in the CNS will provide insight into pathogenic states such as neurodegeneration and brain cancer.
== Overview ==
The overall focus of my laboratory is to understand basic processes in neural development by identifying the key pathways and genes involved and to use this information to provide novel insight into neuropathological disease. Our work will in the long term contribute to improving quality of life by providing new knowledge about nervous system development that can be used to develop strategies to regenerate neural cells and combat neuropathological disease.


=== Insulin signalling in neurogenesis ===
== Regulation of neurogenesis by mTOR signalling and its role in epilepsy ==
Insulin signalling is best known for its role in glucose homeostasis and diabetes. However, this pathway also has critical roles in controlling processes such as cell growth, autophagy and ageing. We have discovered a novel role for the insulin pathway in the temporal control of neurogenesis in Drosophila photoreceptor (PR) neurons (Bateman & McNeill, 2004).


[[Image:Inr.jpg|400px|none|thumb|Photoreceptor differentiation (red) is delayed in insulin receptor clones (marked by the absence of GFP expression]]
We are interested in how the mTOR signal transduction pathway controls neuronal differentiation and the role of this pathway in neurodevelopmental disorders. Hyperactivation of mTOR signalling causes the disease Tuberous Sclerosis Complex (TSC). TSC patients frequently suffer from neurodevelopmental disorders such as epilepsy and autism.


More recently we have shown that insulin signalling interacts with the EGFR pathway in controlling PR cell fate (McNeill et al., 2008). Our current aim is to identify novel genes that are regulated by insulin signalling to control PR neurogenesis.
=== mTOR signalling in neurogenesis ===
mTOR signalling has critical roles in controlling processes such as cell growth, autophagy and ageing. We discovered a novel role for the mTOR pathway in the temporal control of neuronal differentiation in Drosophila photoreceptor neurons (see Bateman & McNeill, 2004).  


[[Image:Inr.jpg|400px|none|thumb|Photoreceptor differentiation (red) is delayed in insulin receptor clones (marked by the absence of GFP expression).]]


=== EGFR signalling in glial maintenance and proliferation ===
EGFR signalling is used reiteratively to control fundamental processes such cell maintenance, differentiation and proliferation. We have shown that the EGFR and insulin pathway interact to control PR cell fate in the developing eye (McNeill et al., 2008). In the developing CNS EGFR signalling is essential for controlling glial maintenance in both Drosophila and vertebrates. We are currently interested in the role of EGFR signalling in glia in the Drosophila post-embryonic CNS.


[[Image:Pnt.jpg|400px|none|thumb|Expression the EGFR pathway gene pointed (red) is upregulated in pten-/- clones (marked by the absence of GFP expression]]
More recently we have identified a novel complex of two proteins, Unkempt and Headcase, that act downstream of mTOR to regulate photoreceptor differentiation in Drosophila (see Avet-Rochex et al., 2014). We are currently study the role of the Unkempt and Headcase in the CNS in Drosophila and mammalian models systems. Understanding the function of these proteins and how they are regulated by mTOR will provide novel insight into how mTOR signalling contributes to neurological disorders like epilepsy and autism.
== Mitochondrial DNA inheritance in the nervous system ==


Mitochondria play critical roles in the generation of cellular energy, apoptosis, cellular calcium buffering and the generation of reactive oxygen species. Mitochondria also have important functions in normal ageing. Given these critical roles in cellular function and physiology, it is not surprising that mitochondria also contribute to a large number of pathogenenic states ranging from cancer to neurodegenerative diseases such as Parkinson’s.  
[[Image:Unkmodel.jpg|400px|none|thumb|A model for the mechanism by which mTOR signalling regulates neuronal differentiation through the Unkempt/Headcase complex.]]


We are interested in how correct mitochondrial DNA (mtDNA) is maintained. Maintenance of correct mtDNA copy number is essential for mitochondrial respiratory function and defects in mtDNA maintenance can cause a group of disorders known as mitochondrial DNA depletion syndrome (MDS). We have recently shown that the mitochondrial inner membrane translocase Tim17 can prevent mitochondrial DNA loss in a cellular model of mitochondrial disease (Iacovino et al., 2009).
== Mitochondrial dysfunction in the nervous system and its role in neurodegenerative disease ==


[[Image:TIM17.jpg|400px|none|thumb|Tim17 (outlined in red) is a component of the TIM23 mitochondrial inner membrane translocase complex]]
Mitochondria are cellular organelles that play vital roles in the generation of cellular energy, apoptosis, cellular calcium buffering and the generation of reactive oxygen species. Mitochondrial dysfunction is increasingly considered to be a critical factor in the development of neurodegenerative disease.


We are interested in how neurons respond to mitochondrial dysfunction and how this process can be modified as a treatment for neurodegenerative disease. We have previously used a genetic screen in yeast to identify genes that can prevent mitochondrial DNA loss in yeast and a cellular model of mitochondrial disease (see Iacovino et al., 2009).


We are currently interested in understanding the mechanism and determining the therapeutic potential of Tim17 in preventing mitochondrial DNA loss. In addition, we are studying how mitochondrial DNA is maintained in the Drosophila CNS.
=== Modelling mitochondrial dysfunction in Drosophila ===


[[Image:Tim17NT2.jpg|400px|none|thumb|Overexpression of Tim17A in human NT2 cells carrying the A3243G mutation prevents mitochondrial DNA loss]]
We are currently developing a Drosophila model of neuronal mitochondrial dysfunction and using this to understand how neurons respond to mitochondrial dysfunction in vivo.
 
[[Image:Larvalflatprep.jpg|400px|none|thumb|The CNS and segmental nerves in a Drosophila larva (marked by GFP expression).]]
 
=== Mitochondrial neuropathology in dementia ===
 
We also use human neurodegenerative disease tissue to study the changes that result from mitochondrial dysfunction in diseases like Parkinson's (see Gatt et al., 2013).

Revision as of 23:20, 6 September 2014

Home        Research        Lab Members        Publications        Links        Lab Stuff        Tools       


Overview

The overall focus of my laboratory is to understand basic processes in neural development by identifying the key pathways and genes involved and to use this information to provide novel insight into neuropathological disease. Our work will in the long term contribute to improving quality of life by providing new knowledge about nervous system development that can be used to develop strategies to regenerate neural cells and combat neuropathological disease.

Regulation of neurogenesis by mTOR signalling and its role in epilepsy

We are interested in how the mTOR signal transduction pathway controls neuronal differentiation and the role of this pathway in neurodevelopmental disorders. Hyperactivation of mTOR signalling causes the disease Tuberous Sclerosis Complex (TSC). TSC patients frequently suffer from neurodevelopmental disorders such as epilepsy and autism.

mTOR signalling in neurogenesis

mTOR signalling has critical roles in controlling processes such as cell growth, autophagy and ageing. We discovered a novel role for the mTOR pathway in the temporal control of neuronal differentiation in Drosophila photoreceptor neurons (see Bateman & McNeill, 2004).

Photoreceptor differentiation (red) is delayed in insulin receptor clones (marked by the absence of GFP expression).


More recently we have identified a novel complex of two proteins, Unkempt and Headcase, that act downstream of mTOR to regulate photoreceptor differentiation in Drosophila (see Avet-Rochex et al., 2014). We are currently study the role of the Unkempt and Headcase in the CNS in Drosophila and mammalian models systems. Understanding the function of these proteins and how they are regulated by mTOR will provide novel insight into how mTOR signalling contributes to neurological disorders like epilepsy and autism.

A model for the mechanism by which mTOR signalling regulates neuronal differentiation through the Unkempt/Headcase complex.

Mitochondrial dysfunction in the nervous system and its role in neurodegenerative disease

Mitochondria are cellular organelles that play vital roles in the generation of cellular energy, apoptosis, cellular calcium buffering and the generation of reactive oxygen species. Mitochondrial dysfunction is increasingly considered to be a critical factor in the development of neurodegenerative disease.

We are interested in how neurons respond to mitochondrial dysfunction and how this process can be modified as a treatment for neurodegenerative disease. We have previously used a genetic screen in yeast to identify genes that can prevent mitochondrial DNA loss in yeast and a cellular model of mitochondrial disease (see Iacovino et al., 2009).

Modelling mitochondrial dysfunction in Drosophila

We are currently developing a Drosophila model of neuronal mitochondrial dysfunction and using this to understand how neurons respond to mitochondrial dysfunction in vivo.

The CNS and segmental nerves in a Drosophila larva (marked by GFP expression).

Mitochondrial neuropathology in dementia

We also use human neurodegenerative disease tissue to study the changes that result from mitochondrial dysfunction in diseases like Parkinson's (see Gatt et al., 2013).

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