Steering Clear of Semaphorins: Neuropilins Sound the Retreat

The evidence that semaphorins function as repulsive The function of the adult nervous system depends critiaxon guidance cues is extensive. Chicken collapsin-1 cally upon precisely sculptured neural circuits. Remark(Coll-1), a secreted semaphorin and the ortholog of the ably, each of the trillions of neurons that comprise the mammalian protein semaphorin III/D (Sema III), can adult nervous system makes functional synaptic confunction in vitro as a collapsing factor for sensory growth nections with one to tens of thousands of target cells. cones. Sema III can also act as a selective chemorepelOne important, albeit somewhat daunting, goal of devellent for several populations of spinal and cranial sensory opmental neurobiologists is the elucidation of molecular and motor axons. Coupled with developmental expresmechanisms that underlie the formation of the intricate sion patterns of Sema III and Coll-1, these data implicate networks of connections between neurons and their tarthis semaphorin as a long-range chemorepellent that gets. Establishment of functional neural connectivity is plays an essential role in the patterning of specific axothe result of a complex combination of activity-indepennal projections. In vivo analysis of semaphorin III mutant dent and activity-dependent developmental processes. mice (discussed below) strongly supports this idea. The activity-independent phase of axon guidance ocMore recently, the structurally related secreted semacurs relatively early during neurodevelopment and relies phorins Coll-3/Sema E and Sema A have also been on the ability of the growth cone, the leading edge of shown to act in vitro as repulsive cues for sympathetic the neuron’s extending axon, to probe its environment neurons (Adams et al., 1997; Feiner et al., 1997). In inverand selectively navigate to its correct target. During this tebrates, secreted Drosophila melanogaster semaprocess, the growth cone encounters a variety of cues phorin II (D-sema II) acts as a repulsive cue for identified that influence its movement either toward or away from motor neurons, underscoring the phylogenetic conserneuronal and nonneuronal tissues. These cues can act vation of secreted semaphorin function during neurodeas attractants or repellents over short or long distances velopment. Approximately one half of all mammalian and can be found on intermediate or terminal targets of semaphorins are transmembrane proteins; however, to any particular axon. The importance of repulsive neudate, only invertebrate transmembrane semaphorins ronal growth cone guidance has long been recognized have been shown to be required during neurodevelopat the cellular level. The recent identification of three ment. Though the cellular basis of semaphorin-mediated phylogenetically conserved gene families, each congrowth cone guidance in a variety of contexts is becomtaining proteins that can act as repulsive guidance cues, ing clearer, how semaphorins signal a change to the has now allowed for extensive experimentation directed neuronal growth cone cytoskeleton in order to affect toward understanding the underlying molecular basis of discrete steering events remains poorly understood. this crucial mode of axon guidance. Neuropilin-1 Is a Semaphorin Receptor Semaphorins, ephrins, and netrins can act as repulRecently, neuropilin, a type 1 transmembrane protein, sive axon guidance cues for specific populations of has been shown to be a receptor, or component of a neurons during development. While receptors for the receptor, for Sema III. Two groups using expression ephrins and netrins have been characterized over the cloning strategies independently found that neuropilin past few years, only recently has a cell surface receptor is a high affinity binding protein for a chimeric protein for a semaphorin been identified. Here, we summarize consisting of Sema III fused at its C terminus to secreted the current understanding of the role played by neuropiplacental alkaline phosphatase (Sema III-AP) (He and lins asreceptors, or components of receptor complexes, Tessier-Lavigne, 1997; Kolodkin et al., 1997). Neuropilin for members of the semaphorin family of axon guidance is required for Sema III chemorepulsive and growth cone molecules. collapsing functions, since antibodies directed against Semaphorins Are Repulsive Growth Cone neuropilin inhibit these functions of Sema III on sensory Guidance Cues neurons in vitro. Importantly, growth cones of sensory The semaphorins belong to a family of phylogenetically neurons cultured from mice lacking an intact neuropilin conserved proteins, several members of which can act gene do not collapse upon application of Sema III (Kitsuas repulsive cues for specific populations of neurons kawa et al., 1997). These results demonstrate that neuduring development (Mark et al., 1997). The semaphorin ropilin is the receptor or an essential component of the family is very large. For example, the human genome receptor for the axon guidance cue Sema III. encodes more than 20 distinct semaphorins. SemaNeuropilin was first identified as a membrane protein phorins include both secreted and transmembrane glyexpressed in the developing tectum of Xenopus laevis, coproteins, suggesting that some semaphorins influand this protein has been extensively characterized by ence growth cone guidance at a distance, while others Hajime Fujisawa and colleagues (reviewed in Fujisawa act locally. Semaphorins are defined by a conserved et al., 1997). Since neuropilin is the founding member