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Posted on Oct 09, 2006, 8 a.m.
By Bill Freeman
Long regarded as unyielding territory by neurobiologists and neurologists alike, the capacity of the adult central nervous system (CNS) for growth is at last being revealed, along with its limitations. Just within the past few years scientists have discovered that neurons
Long regarded as unyielding territory by neurobiologists and neurologists alike, the capacity of the adult central nervous system (CNS) for growth is at last being revealed, along with its limitations. Just within the past few years scientists have discovered that neurons—the information-processing cells of the brain—can multiply in the adult, an idea that was previously unheard of. Adult neurons can also form new axons, the long extensions that allow neurons to form connections and thereby communicate. With this new understanding comes the need to identify growth-promoting signals. If such signals could be controlled, it might be possible to spur the establishment of new connections between neurons and, ultimately, to treat previously incurable neurological problems.
New insights about axonal growth come partially from studies of inhibitory molecules that thwart the growth process by blocking axons' ability to extend after injury. Further knowledge comes from studies of development, since signals and molecules that help the CNS to establish its connections could similarly promote growth in the injured CNS.
At the March 20, 2006, meeting of the Neurodegenerative Diseases Discussion Group, organized by Marie Filbin of Hunter College, three scientists discussed the failure and capability of adult CNS axons to sprout and to grow after injury, as well as developmental processes that govern axonal growth.
Stephen Strittmatter of Yale University described the roles of the Nogo protein and its receptor in restricting adult CNS plasticity and regeneration. Nogo is found in myelin, and evidence for its role in the myelin-induced inhibition of axon outgrowth comes from studies of Nogo or Nogo receptor knockout mice. It further appears that the inhibitory properties of Nogo differ depending on the axonal fiber system being studied. Despite its tendency to thwart CNS regeneration, Nogo may have an interesting functional role: preventing axonal growth following critical periods of nervous system development.
Glenn Yiu of Harvard Medical School further reviewed signaling mechanisms related to the Nogo system that contribute to the inhibition of axon regeneration in the adult CNS. The Nogo receptor uses the coreceptors p75 and LINGO-1 for signaling. Another coreceptor, called TROY, can act as a substitute for p75 in the Nogo receptor complex. LINGO-1, the Nogo receptor, and TROY collaborate to induce intracellular signaling, such as activation of Rho, leading to axon outgrowth inhibition.
Finally, Christopher Henderson of Columbia University talked about the influence of a growth factor called glial cell line-derived neurotrophic factor (GDNF) on motor neuron axonal growth during development in one specific system. GDNF regulates expression of the transcription factor PEA3, and both are necessary for the normal innervation of the CLMD muscles during development. Separate from its influence on PEA3, GDNF also guides motor neuron axonal growth. In addition to GDNF and PEA3, several other systems may collaborate to help motor neuron axons innervate appropriate target muscles.
By focusing on specific inhibitory molecules and growth-promoting factors, these researchers have identified neurobiological mechanisms that may promote or prevent axonal extension. Further studies are underway to better understand these targets, and, ultimately, to exploit this knowledge for the treatment of neurological disease and injury.
