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

Neurons have unique structural and functional polarity. In general, information flows from the short dendrites to the long axon, and each neuron has multiple 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, however, about the nature of the underlying molecular events. New data strongly suggest that actin depolymerization at a growth cone is crucial for axon fate determination. We hypothesize that an autocatalytic positive feedback loop at all growth cones locally regulates actin dynamics and other cellular events required for axon formation. Meanwhile, a negative feedback signal, produced by the positive feedback loop, propagates from all growth cones throughout the neuron and counteracts the positive feedback loops. Such feedback regulation provides a robust mechanism for spontaneous symmetry breaking and the formation of only one axon, even in a symmetric in vitro environment. Based on data from studies of cell migration, axon guidance, vesicle exocytosis, and the regulation of actin and microtubule polymerization, we propose a molecular scheme for the positive feedback loop and discuss possible negative feedback signals. BioEssays 22:172-179, 2000.