Novel finding in yeast gives insight into neurofibromatosis
1
Newsdesk http://neurology.thelancet.com Vol 5 August 2006 649 notch ligands, all new cells generated were found in the cerebral cortex at 45 days and were negative for glial fibrillary acidic protein—an indicator for mature CNS cells. These results show that cells stimulated by Notch ligands could survive for long periods in the immature state. To determine the regenerative responses of Notch ligands the researchers stimulated focal ischaemia in the cerebral cortex of rats. Exogenous proteins were delivered by osmotic pump and tests were used to monitor motor behaviour over a 45-day period. The investigators reported that new cells were found in the ipsilateral and contralateral subventricular zones. Very few of these cells were differentiated neurons or astrocytes and there was a significant improvement in the motor skills of the rats. Mark Mattson from the National Institute on Aging, Baltimore (MD, USA) thinks this is an important study because the researchers provide evidence that activation of Notch can increase neural progenitor cells in a rat model of the injured adult brain, which suggests an important role for Notch during repair and will have important therapeutic implications. However, Mattson does point out that Notch is expressed by several different types of cells in the brain where it is involved in normal function as well as injury responses. “For example, Notch is present in neurons where it plays an important role in synaptic plasticity and learning and memory”, said Mattson. “In the present study the authors found that, although Notch activation did not reduce the amount of brain damage in a stroke model in which the middle cerebral artery was permanently occluded, it did improve functional outcome. This could be the result of enhanced plasticity of existing neurons, rather than enhanced neurogenesis suggested by the authors.” McKay hopes that signal transduction in stem cells will become a focus in regenerative and cancer medicine; he also hopes that the attention of the cancer drug industry—which is largely concentrated on the development of tyrosine kinase inhibitors—will shift to the Notch signalling pathway. Nayanah Siva Novel finding in yeast gives insight into neurofibromatosis Neurofibromatosis type 1 (NF1) is a genetic disorder characterised by the formation of multiple tumours affecting the nervous system. Researchers have now identified a new protein “brake” that seems to inhibit the proliferation of tumour cells. This discovery could provide clues to how the disease develops and would possibly lead to the development of new treatments. “Saccharomyces cerevisiae has been an outstanding model system for elucidating how cells send response signals”, says lead investigator Joseph Heitman (Duke University, Durham, NC, USA). “That is the background for this type of study, to understand how a single cell organism responds to an extracellular cue, which in this case is glucose.” Previously, Heitman and colleagues identified the novel kelch protein, which functions in the signalling pathway. It was clear they had an unknown target, says Heitman, and “by using yeast as a model system, we were able to identify the target proteins that function in glucose signalling and cell morphological control”. The target proteins were Ira1 and Ira2, which are structural and functional homologues to neurofibromin, the human protein in NF1. Neurofibromin inactivates Ras signalling and constrains cell growth. “These proteins shut off the growth promoting signal that emanates from Ras”, explains Heitman, “and that is why when there is loss of neurofibromin function in specific cells, there are consequences for patients—one of which is an increased risk of tumour formation.” The central finding of the current study is the discovery that two novel proteins, Gpb1 and Gbp2, control the activity of the neurofibromin homologues Ira1 and Ira2. They seem to be necessary for the Ira proteins’ ability to regulate Ras. “What we know from previous studies is that when we discover something in yeast, there may be a connection with mammalian cells”, says Heitman. “We don’t know if that will be the case here, but our working hypothesis is that there may be kelch proteins in mammalian cells that interact with neurofibromin, and this may provide a new way of approaching patients with NF1.” While this is very exciting basic science, with a potential relation with NF1 biology, comments David Gutmann (Washington University School of Medicine, St. Louis, MO, USA), “its application to NF1 awaits the establishment of a direct mechanistic connection to neurofibromin function”. If this pathway exists in mammalian cells, this discovery could lead to the development of a new class of drugs for treating tumours in patients with this disease, he added. Roxanne Nelson Yeast studies might help understand neurofibromatosis Paul Barker/Science Photo Library We do not have the rights to reproduce this image on the web.
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Transcript of Novel finding in yeast gives insight into neurofibromatosis
Newsdesk
http://neurology.thelancet.com Vol 5 August 2006 649
notch ligands, all new cells generated were found in the cerebral cortex at 45 days and were negative for glial fi brillary acidic protein—an indicator for mature CNS cells. These results show that cells stimulated by Notch ligands could survive for long periods in the immature state. To determine the regenerative responses of Notch ligands the researchers stimulated focal ischaemia in the cerebral cortex of rats. Exogenous proteins were delivered by osmotic pump and tests were used to monitor motor behaviour over a 45-day period. The investigators reported that new cells were found in the ipsilateral and contralateral subventricular zones. Very few of these cells were diff erentiated neurons or astrocytes and there was a signifi cant
improvement in the motor skills of the rats.
Mark Mattson from the National Institute on Aging, Baltimore (MD, USA) thinks this is an important study because the researchers provide evidence that activation of Notch can increase neural progenitor cells in a rat model of the injured adult brain, which suggests an important role for Notch during repair and will have important therapeutic implications. However, Mattson does point out that Notch is expressed by several diff erent types of cells in the brain where it is involved in normal function as well as injury responses. “For example, Notch is present in neurons where it plays an important role in synaptic plasticity and learning and memory”, said Mattson.
“In the present study the authors found that, although Notch activation did not reduce the amount of brain damage in a stroke model in which the middle cerebral artery was permanently occluded, it did improve functional outcome. This could be the result of enhanced plasticity of existing neurons, rather than enhanced neurogenesis suggested by the authors.”
McKay hopes that signal transduction in stem cells will become a focus in regenerative and cancer medicine; he also hopes that the attention of the cancer drug industry—which is largely concentrated on the development of tyrosine kinase inhibitors—will shift to the Notch signalling pathway.
Nayanah Siva
Novel fi nding in yeast gives insight into neurofi bromatosisNeurofi bromatosis type 1 (NF1) is a genetic disorder characterised by the formation of multiple tumours aff ecting the nervous system. Researchers have now identifi ed a new protein “brake” that seems to inhibit the proliferation of tumour cells. This discovery could provide clues to how the disease develops and would possibly lead to the development of new treatments.
“Saccharomyces cerevisiae has been an outstanding model system for elucidating how cells send response signals”, says lead investigator Joseph Heitman (Duke University, Durham, NC, USA). “That is the background for this type of study, to understand how a single cell organism responds to an extracellular cue, which in this case is glucose.”
Previously, Heitman and colleagues identifi ed the novel kelch protein, which functions in the signalling pathway. It was clear they had an unknown target, says Heitman, and “by using yeast as a model system, we were able to identify the target proteins that function in glucose signalling and cell morphological control”.
The target proteins were Ira1 and Ira2, which are structural and functional homologues to neurofi bromin, the human protein in NF1. Neurofi bromin inactivates Ras signalling and constrains cell growth. “These proteins shut off the growth promoting signal that emanates from Ras”, explains Heitman, “and that is why when there is loss of neurofi bromin function in specifi c cells, there are consequences for patients—one of which is an increased risk of tumour formation.”
The central fi nding of the current study is the discovery that two novel proteins, Gpb1 and Gbp2, control the activity of the neurofi bromin homologues Ira1 and Ira2. They seem to be necessary for the Ira proteins’ ability to regulate Ras.
“What we know from previous studies is that when we discover something in yeast, there may be a connection with mammalian cells”, says Heitman. “We don’t know if that will be the case here, but our working hypothesis is that there may be kelch proteins in mammalian cells that interact with neurofi bromin, and this may provide a new way of approaching patients with NF1.”
While this is very exciting basic science, with a potential relation with NF1 biology, comments David Gutmann (Washington University School of Medicine, St. Louis, MO, USA), “its application to NF1 awaits the establishment of a direct mechanistic connection to neurofi bromin function”.
If this pathway exists in mammalian cells, this discovery could lead to the development of a new class of drugs for treating tumours in patients with this disease, he added.
Roxanne Nelson
Yeast studies might help understand neurofi bromatosis
Paul
Bar
ker/
Scie
nce
Phot
o Li
brar
y
We do not have the rights to reproduce this image on the
web.
