Progress in Brain Research, Vol. 147 ISSN 0079-6123 Copyright ß 2005 Elsevier BV. All rights reserved CHAPTER 7 Competition in neurite outgrowth and the development of nerve connections Arjen Van Ooyen * Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands Abstract: During the development of the nervous system, neurons form their characteristic morphologies and become assembled into synaptically connected networks. In both neuronal morphogenesis and the development of nerve connections, competition plays an important role. Although the notion of competition is commonly used in neurobiology, there is little understanding of the nature of the competitive process and the underlying molecular and cellular mechanisms. In this chapter, we review a model of competition between outgrowing neurites, as well as various models of competition that have been proposed for the refinement of connections that takes place in the development of the neuromuscular and visual systems. We describe in detail a model that links competition in the development of nerve connections with the underlying actions and biochemistry of neurotrophic factors. Introduction During the development of the nervous system, neurons form their characteristic morphologies and become assembled into synaptically connected net- works. In many of the developmental phases that can be distinguished, competition plays an important role. Axonal and dendritic morphogenesis Neurons start growing out by projecting many broad, sheet-like extensions, called lamellipodia, which subsequently condense into a number of small, undifferentiated neurites of approximately equal length (Dotti et al., 1988). Eventually, one of the neurites (usually the longest) increases its growth rate — while at the same time the growth rate of the remaining neurites is reduced — and differentiates into an axon. All the neurites have the potential to develop into the axon (Dotti and Banker, 1987; Goslin and Banker, 1989; Bradke and Dotti, 2000a). In experiments in which the axon is transected at various distances from the soma, the longest neurite remaining after transaction usually becomes the axon, regardless of whether it was previously an axon or a dendrite (Goslin and Banker, 1989). Thus, axonal differentiation appears to be a competitive process in which the growth rate of the longest neurite is accelerated at the expense of all the other neurites, whose growth become inhibited (Dotti et al., 1988; Goslin and Banker, 1990; Bradke and Dotti, 2000b). These slower growing neurites become differentiated as dendrites. The development of dendritic morphology proceeds by way of the dynamic behavior of growth cones — specialized structures at the terminal ends of outgrowing dendrites that mediate elongation and branching. Competition between dendrites is expected to occur with respect to elongation: the proteins upon which elongation depend (e.g., tubulin and microtubule-associated proteins) are produced in the soma and need to be divided between all the growing dendrites of a neuron. Competition could *Corresponding author. Tel.: +31 20 5665483; Fax: +31 20 6961006; E-mail: A.van.Ooyen@nih.knaw.nl DOI: 10.1016/S0079-6123(04)47007-1 81