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Growth and survival in the nervous system

Nervous response

(December 16, 1999, Gazette)

Dr. Karen Mearow

Photo by HSIMS

By Sharon Gray

Dr. Karen Mearow, Medicine, is involved in basic research on the developing and mature nervous system. In particular she is investigating how the nervous system responds to injury – why some cells die and others survive and are able to regenerate damaged nerve fibres.

Neurons, as the basic functional unit of the nervous system, are very specialized cells that are responsible for all sensation and direction of movement in the body. Each of these nerve cells extends a projection (the axon) that connects it with either muscle or other neurons; the axons are the route for information sent both to and from the brain and spinal cord. It is these connections among neurons and other tissues which provide the necessary wiring for all functions of the nervous system. In addition, in many cases these connections are also required for the continued survival of the neurons.

Following injury to the nervous system, some nerve cells and their fibres can be damaged to such an extent that they do not recover, while others do recover and may be able to regenerate their fibres under the right circumstances. However, since most neurons are not able to divide to produce new neurons, neurons that are lost following injury, disease or even normal aging are not replaced.

“One major focus of research in my field is understanding how to prevent this loss and how to promote the regrowth of damaged nerve fibres and the ultimate recovery of function,” said Dr. Mearow. “One way of doing this is to understand the basic mechanisms required for normal cell survival and fibre growth and how these can be disrupted following stress or damage.”

Dr. Mearow’s work centres on a group of compounds known as the neurotrophins, in particular nerve growth factor (NGF). The developing nervous system requires these factors for their early differentiation and survival as well as the formation of appropriate connections with their target tissues (e.g. other neurons, muscle, skin). For many types of neurons this dependence on the neurotrophins for both survival and formation and maintenance of connections extends through adulthood. However, for one group of neurons, the sensory neurons in the peripheral nervous system, while the very young neurons require the factors for survival, the older neurons do not.

One area of Dr. Mearow’s research is to investigate how NGF regulates this survival response as well as being involved in promoting nerve fibre regeneration. She is concerned with whether the young neurons use the same signaling pathways as the adult neurons. A signaling pathway defines how the neuron will respond to the growth factor. The NGF binds to specific receptors on the nerve cell surface and this sets off a series of biochemical steps that result in a particular cellular response – whether it be survival or neurite initiation.

“It’s like turning on a radio and getting a sound at the end,” she explained. “You can turn the radio on with the power switch, but you also have the choice of a number of different stations depending upon where you live and you can also turn the volume up or down.

“In our system, the receptors are defined and many of the individual components of the signaling pathways are also known. But even though the young and adult neurons have the same receptors and many of the same signaling components, they don’t require the same pathways for survival. We want to know why this is – we want to find the key point where if you block one component, you lose the survival or growth response”

Dr. Mearow describes her work as similar to putting together a puzzle, except that sometimes you don’t know what the pieces are or how they fit together. Working primarily with neurons in tissue cultures, she and her research group have found that neonatal sensory neurons require NGF for survival and that a particular signaling pathway is activated and required for this response. In contrast, within one to two weeks after birth of the animal, these same neurons no longer need NGF to keep them alive – they do need it for putting out their axons, however. Although the same signaling pathways are active in the mature neurons, they appear to be activated differently and it may be that other pathways interact with the NGF-activated signals to keep these adult neurons alive.

“One other interpretation is that there are both ‘life’ and ‘death’ pathways,” said Dr. Mearow. “In the young neurons the ‘death’ pathway may be the default and these cells require activation of the ‘life’ pathway by NGF to suppress the ‘death’ pathway. In the adult neurons, it is possible that the ‘death’ pathway is no longer as active, and therefore signaling along the NGF ‘life’ pathway is no longer critical for survival.”

Because NGF and other trophic (nutritional) factors are important in the normal development and function of the nervous system as well as during aging or after injury, Dr. Mearow hopes that her research will contribute to understanding how neurons respond to damage and how trophic factors can be used to keep cells alive longer or enhance nerve regeneration.

Dr. Mearow’s research recently received a three-year Medical Research Council of Canada grant, and her funding from the Natural Sciences and Engineering Research Council of Canada has been renewed for a further four years.