Manipulation of integrin gene activates adult nerve cell regeneration

LONDON Manipulating the integrin gene can dramatically switch adult neurons on to regenerate. In 1 July Journal of Neuroscience, Maureen Condic shows that injured adult neurons engineered to express increased levels of integrin can re-grow to a similar degree as embryonic or postnatal neurons. The finding suggests that engineered adult neurons may be useful in the treatment of various clinical conditions, such as damage from stroke, spinal cord injury and other neurological conditions. One of the great unsolved mysteries of neuronal growth has been why embryonic or young neurons have the ability to regenerate whereas adult cells do not. Previous studies had suggested that this could be attributed to the poor environment that the adult central nervous system (CNS) provides to support growth and that improving this environment could stimulate adult neuron regeneration. The adult CNS expresses very low levels of growth-promoting matrix molecules and high levels of myelin-associated factors that inhibit the growth of axons. Also, after injury, there is a pronounced upregulation of inhibitory proteoglycans that are not normally expressed in the mature brain. Other studies have suggested the environment is unlikely to be the only factor that inhibits adult neurons regenerating, because there are maturation-associated changes in the inherent ability of adult neurons to regrow. It has also been demonstrated that when embryonic neurons are transplanted into the injured adult CNS, they show significant outgrowth despite being in this 'inhibitory environment'. One cellular factor that could potentially influence neuronal re-growth is a group of proteins known as the integrins, which are receptors that mediate axon extension in both embryonic and adult neurons. Integrin expression is known to be very high in embryonic and postnatal neurons, but this expression declines to low levels in adult CNS tissues. Increased integrin expression has also been shown to mediate adaptation of embryonic neurons to inhibitory environments and has been correlated with superior neurite extension. To investigate whether integrin could be an essential component in neuronal regeneration, Condic, from the Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, USA, used a modified adenovirus to insert extra copies of a gene for integrin α1β1, the primary laminin receptor in sensory neurons, into sensory neuronal cultures derived from the dorsal root ganglia of adult rats. A second group of neurons received extra copies of a different integrin gene, α5β1, a major fibronectin receptor, while a third group received the β-galactosidase gene. The adenoviral infection was manipulated to yield levels of integrin in the adult neurons comparable to those in newborn animals. When the neurons were tested for adaptation in conditions similar to those of the adult CNS after injury, adult neurons expressing high levels of either integrin had a much greater outgrowth compared to the other adult neurons. This improvement in growth was quite pronounced, representing up to a 2.5-fold increase in the number of neurites per cell and a 10-fold increase in neurite length compared with controls. It was also specific for the receptor-type that was expressed; increased expression of integrin α1β1 was associated with increased outgrowth on laminin but not on fibronectin. This increase in nerve fibre growth occurred even in environments that would otherwise prevent regeneration, such as the presence of inhibitory molecules and on weakly growth-promoting substrata. And neurons showed improved growth when tested on both high and low levels of extracellular matrix ligands compared to β-galactosidase expressing neurons. This suggests that, in a similar manner to early, postnatal neurons, adult neurons with high levels of integrin expression are able to adapt to different substrata by regulating integrin expression.There were fears that despite this substantial improvement in growth, the performance of adult neurons might be significantly inferior compared to that of younger neurons under the same conditions. However, when Condic compared the outgrowth of the engineered adult neurons with that of early postnatal neurons, it was virtually indistinguishable. The dramatic effect of increasing integrin expression on neuronal growth levels was very surprising, Condic said. Many scientists had previously believed that the inherent limitations on growth of nerve fibres from adult neurons were too complex to be significantly affected by altering a few genes. "It's as though you have a car on blocks in the front yard, and it has all the necessary components except for its wheels," explained Condic. "If you give the wheels back, which are the car's usual way of interacting with the environment, it's ready to go." Integrin proteins are like the tyres of the car - they connect with the surrounding surface to enable neurons to extend nerve fibres, she suggested. The findings will provide a complimentary approach to studies of factors in the nervous system environment that improve regeneration, Condic argued. In the future, effective therapies will probably employ a multi-pronged approach that changes environmental factors as well as the inherent properties of the neurons. However, the major advantage of targeting the cells is that it should be much easier to regulate gene expression in specific neurons than to modify the environment of the CNS. "The nervous system is a very big place, and right now we don't have the technology to modulate the total environment of the brain," Condic explained. Because the nervous system is so complex, there is also a risk that changes to the environment of the brain could inadvertently harm neurons outside of the damaged area and result in problems such as epilepsy or increased sensitivity to pain. It may eventually be possible to modify integrin genes with a type of 'switch' controlled by drugs or other chemicals, and inject those genes into a damaged area of the brain, proposed Condic. Treating physicians could then add and subtract the chemical to turn the genes on and off, allowing precise control the amount of nerve fibre growth in the affected region of the brain. But, Condic admitted this approach is still some way off and more research is needed before scientists can predict whether such a technique might work in humans. Her research group are now planning to study integrin gene expression in an animal model for a common type of spinal cord injury. "This is the next critical step," she said. "At this point, all systems look 'go' with blazing green lights — but in animals, it's much more complicated."

Manipulation of integrin gene activates adult nerve cell regeneration

Manipulating the integrin gene can enable adult neurons to switch on the molecular mechanisms necessary to allow regeneration.

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