Nerve growth dynamics. Quantitative models for nerve development and regeneration.

Abstract

The quantitative analysis of nerve growth dynamics is critical to our understanding of nerve development and regeneration, but only recently has a quantitative framework begun to emerge to help define key objectives and to direct experimental measurements towards achieving this goal. Conceptually, the framework centers on the dynamic processes commonly observed for individual growth cones of growing neurites at the phase microscopy level, namely lamellipodial and filopodial extension and retraction. Because these activities essentially define the position of the axon tip, understanding how they are regulated offers to yield direct insight into factors governing the growth trajectory of the axon. In addition, much biological interest and effort is focused on the lamellipodial and filopodial behavior of the growth cone, which should facilitate experimental quantitation. Characterization of lamellipodial and filopodial activity has not been straightforward, however, because their inherent randomness leads to a requirement for considerable data and for less common mathematical techniques, such as time-series analysis. The work reviewed above has identified key analytical tools and experimental parameters needed to develop an integrated model of growth cone dynamics. Detailed measurement and analysis will be required to carry this development process to the next step. The cellular model of growth cone motility resulting from the characterization of lamellipodial and filopodial dynamics represents an intermediate description that can be extended to encompass both molecular mechanisms of growth cone behavior and axonal growth in multicellular tissue environments. For example, on the molecular level, filopodia contain a central core of actin filaments whose polymerization and depolymerization is thought to correspond to filopodial extension and retraction, with significant regulation possible through receptor-mediated effects on actin dynamics. By rewriting the parameters of filopodia dynamics in the current model in terms of these molecular events, one can begin to investigate their effects on growth cone behavior and to examine hypotheses of molecular mechanisms. Processes underlying lamellipodial behavior can be examined in a similar manner. At the tissue level, the effects of environmental factors on model parameters can be incorporated to yield predictions of the neurite outgrowth response to a particular environment. Such predictions offer a basis for designing microenvironments with optimal characteristics for enhancing nerve regeneration or manipulating the nerve growth response. Although the quantitative framework described here has focused on growth by peripheral nerve cells, it represents concepts known to apply to neurons of the central nervous system, as well.(ABSTRACT TRUNCATED AT 400 WORDS)