Axons are the long, slender projections of nerve cells whose growth is governed by the intrinsic properties of neurons as well as by growth-promoting and growth-inhibiting molecules present in the neurons’ environment. In fish, the injured axons of the central nervous systems are able to regenerate. This is not the case in mammals, and therefore humans. A group of researchers led by Prof. Dr. Claudia Stürmer at the University of Konstanz is focusing on the question as to how growing axons are able to find their final destination. The researchers have found that the prion proteins that cause mad cow disease (bovine spongiform encephalopathy, BSE) also affect the development of nerve fibres.
Growing axons move through their environment by using the growth cone at their tip. As the growth cone moves forward, it adds new material to the cell membrane and so extends the axon. The Reggie-1 and Reggie-2 proteins, which are essential for axon growth and regeneration, were discovered using a monoclonal antibody that was developed around 20 years ago. In fish it has been found that optic nerve injury leads to the upregulation, i.e. re-expression of the two proteins. “We now know that Reggie-1 and Reggie-2 are present in high concentrations in growing axons as well as in the neurons from which they originate,” said Claudia Stürmer, head of the Department of Developmental Neurobiology at the University of Konstanz.In adult mammals, when axons are severed, neurons of the central nervous system are only able to produce Reggie proteins to a limited extent, or not at all. However, in contrast to mammals, and therefore humans, fish are able to regenerate CNS neurons, including retinal ganglion cell axons when the optic nerve is severed. “Fish neurons produce large quantities of Reggie proteins, which enables new growth cones to be formed and axons to regenerate,” Stürmer explained. The researchers found that the temporary blinding (e.g., by severing the optic nerve) of fish led to the lesion-induced expression of Reggie proteins which resulted in the restoration of vision in the fish.
Experiments with living fish and cell cultures were carried out to down-regulate, i.e. suppress the re-expression of Reggie proteins, which led to axons losing their regenerative ability. “The severed neurons are unable to develop growth cones and axons cannot grow,” said Claudia Stürmer, adding, “we now know that the Reggie proteins are essential for the recruitment of membrane and cargo proteins to specific sites of the plasma membrane, such as the growth cone of elongating axons." These findings have shown that Reggie proteins control fundamental growth processes. It is important to note that they not only have this role in neurons, but in any polarizing cell,” said Stürmer.
The researchers are also investigating the effects of other proteins on axon growth. Stürmer and her team are also studying the prion protein, which plays a major role in diseases such as bovine spongiform encephalopathy (BSE), commonly known as mad cow disease. They have chosen the prion protein as it has been found to interact with Reggie proteins and support axonal growth. It is known that the Thy-1 protein, an abundant neuronal glycoprotein in mammals, interacts with the Reggie proteins. However, just how this affects the growth of axons is not yet known. On the other hand, Dr. Martin E. Schwab from Zurich has identified Nogo as a potent inhibitor of axon growth: Nogo prevents the regenerative ability of mammalian and human axons. As fish can regenerate axons, the researchers suspected Nogo to be absent in the brain of fish. “However, we now know that the visual system of fish contains a short form of “Nogo” and that this does not inhibit regeneration,” explained Stürmer.
Claudia Stürmer became interested in how growth cones are controlled by specific molecules or forced to collapse when she first visited Prof Dr. Friedrich Bonhoeffer at the Max Planck Institute of Developmental Biology in Tübingen where she was able to observe the tips of growing axons ‘live’ under time-lapse video microscopes. Claudia Stürmer earned her doctoral degree in 1978 for her work on the regeneration of axons in the visual systems of fish at the Institute of Biology III under the supervision of Prof. Dr. José Campos-Ortega. She spent her postdoctoral study periods in Prof. S. S. Easter’s lab in Ann Arbor (Michigan, USA) and at the Max Planck Institute in Tübingen investigating how axons find their way to their final destination and why axons of the visual system of fish are able to regenerate. She has been head of the Department of Developmental Neurobiology at the University of Konstanz since 1991.
Investigations carried out by the Konstanz researchers into the effect of proteins such as Reggie on axon regeneration has led to further insights: the researchers found that fish have a shorter form of the ‘RTN-4/Nogo’ protein than mammals, and that this protein lacks the inhibitory Nogo-A-specific domain and does not interfere with axon growth. Recently, the researchers have identified a Nogo-A homologue, RTN-6, in fish. Further analyses showed that RTN-6 contained the Nogo-A-specific domain and that genome duplication has led to the emergence of this protein. The researchers are currently focusing on elucidating the function of this protein and hope that the results will provide them with interesting insights. “However, the identification of RNT-6 has made it possible to investigate the evolutionary origin of mammalian Nogo-A,” said Claudia Stürmer.
The findings relating to the function of Reggie proteins could be of huge importance in the field of neurology. Therefore, Prof. Stürmer’s group of researchers is working with Prof. Dr. Bähr’s group at the Department of Neurology at the University Hospital of Göttingen. The joint efforts have already led to the finding that severed axons of the visual system of rats are able to regenerate by inducing the expression of Reggie proteins in ganglion cells using viral vectors. “We will carry out similar experiments with neurons and axons in other areas of the central nervous system to find out whether the expression of Reggie also affects axonal regeneration in these areas,” concludes Claudia Stürmer.
Prof. Dr. Claudia StürmerUniversity of KonstanzFaculty of BiologyDevelopmental NeurobiologyTel.: +49 (0) 7531/ 88 2236Fax: +49 (0) 7531/ 88 3894E-mail: claudia.stuermer(at)uni-konstanz.de