Axon formation: a molecular model for the generation of neuronal polarity

Neurons have unique structural and functional polarity. In general, informa tion flows from the short dendrites to the long axon, and each neuron has m ultiple dendrites but only one axon. A detailed description of the cellular events leading to the establishment of axonal-dendritic polarity has been given from an in vitro hippocampal culture model system, Little is known, h owever, about the nature of the underlying molecular events. New data stron gly suggest that actin depolymerization at a growth cone is crucial for axo n fate determination. We hypothesize that an autocatalytic positive feedbac k loop at all growth cones locally regulates actin dynamics and other cellu lar events required for axon formation. Meanwhile, a negative feedback sign al, produced by the positive feedback loop, propagates from all growth cone s throughout the neuron and counteracts the positive feedback loops. Such f eedback regulation provides a robust mechanism for spontaneous symmetry bre aking and the formation of only one axon, even in a symmetric in vitro envi ronment. Based on data from studies of cell migration, axon guidance, vesic le exocytosis, and the regulation of actin and microtubule polymerization, we propose a molecular scheme for the positive feedback loop and discuss po ssible negative feedback signals. (C) 2000 John Wiley & Sons, Inc.