THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES Molecular Interactions Modulating Neuronal Survival and Growth

The extracellular environment of the neuron provides a heterogeneous milieu of survival and growth modulating molecular species subserving regulatory signals that operate in development, meditate activity-dependent enduring changes in synaptic connectivity, and promote or inhibit survival and axonal regeneration following insult. Parallel distributed processing networks in neurons, activated by these molecular species, can likely be recruited selectively to serve specific needs of the organism. RESUME: Interactions moleculaires modulant la survie et la croissance neuronale. L'environnement du neurone fournit un milieu heterogene d'especes moleculaires modulant la survie et la croissance, favorisant les signaux regulateurs qui agissent sur le developpement, qui servent de m^diateurs produisant des changements persistants, dependants de I'activite, dans la connectivite synaptique et favorisent ou inhibent la survie et la regeneration axonale a la suite d'une agression. Des reseaux de traitement de 1'information, distribues en parallele dans les neurons, peuvent vraisemblablement etre recrutes selectivement pour remplir certains besoins specifiques de l'organisme lorsqu'ils sont actives par ces especes moleculaires. Can. J. Neurol. Sci. 1991; 18: 398-402 Perhaps the two greatest challenges of contemporary neurobiology are the elucidation of the identity and mode of action of those critical biological processes that underlie neural cell injury and curtail or enhance regeneration, and the manipulation of neural responses that can contribute to recovery following damage to the central nervous system. There now exists a body of compelling experimental data that refutes accepted dogmas that injury to the mature mammalian CNS is irreversible and that regeneration does not occur. With respect to neuronal cells of the CNS, different populations have the intrinsic capacity to initiate and sustain extensive axonal regrowth that can restore functional reconnectivity with distant targets. These neurons, like others in the peripheral nervous system, appear to be responsive to molecular species in the axonal environment that can inhibit or enhance regeneration. Furthermore, injured neurons, in response to environmental cues, have the capacity to reorganize neuronal circuitry in a functionally appropriate manner as a result of sprouting of new processes from their axons. The thrust of this brief review is to describe some of those molecular species in the axonal environment that influence survival of neurons and regenerative and sprouting responses of axons. The text will highlight recent contributions of the authors to this endeavor, but the reader is directed to comprehensive reviews of the subject matter. Molecular Interactions Subserving Neuron Survival and Modulation of Process Formation There is increasing evidence that two broad categories of molecular species contribute to neuron survival and process elongation or growth inhibition by virtue of interactions with neurons singly and as complexes. These two categories are (1) immobilized molecular species of the extraneuronal milieu (extracellular matrix and cell surfaces in juxtaposition to the axon) that promote or inhibit adhesion and neurite extension by local interactions at the growth cone; and (2) diffusible factors that exert effects following axonal uptake and, in some cases, retrograde axonal transport to the cell body. Examples of immobilized species that promote adhesion and neurite growth are laminin, fibronectin, proteoglycans, and collagen. Two glycoproteins of molecular mass 250 kDa and 35 kDa have been implicated in inhibition of neurite growth. The best characterized diffusible molecules are members of the Nerve Growth Factor family, which include NGF, BDNF, and NT3 (reviewed in 2). Other neurotrophic factors, such as ciliary neurotrophic factor (CNTF) and the fibroblast growth factor family (FGF), do not appear to be retrogradely transported, and FGF may exert its effects as a complex with proteoglycan. In addition, a number of neurotransmitters have been implicated in neurite growth and growth inhibition (reviewed in 3). From the Department of Medicine, (R.J.R.), and the Department of Pediatrics, (K.E.D.), Queen's University, Kingston, and the Department of Surgery, McGill University, Montreal, (V.M.K.V., P.M.R.) Reprint requests to: Dr. R.J. Riopelle, Apps Medical Research Centre, Kingston General Hospital, Kingston, Ontario, Canada K7L 2V7