Attraction versus Repulsion Modular Receptors Make the Difference in Axon Guidance

not encode any obvious signal transducing motifs. However, they do encode proline-rich motifs that are evolutionarily conserved and may bind adaptor molecules linking these receptors to signal transduction pathways. An interesting scenario exists at the midline: CNS midMark A. Seeger*‡§ and Christine E. Beattie†‡§ *Department of Molecular Genetics †Department of Pharmacology ‡Neurobiotechnology Center Ohio State University Columbus, Ohio 43210 line cells express both attractants and repellents, and many growth cones near the midline simultaneously express both Fra and Robo receptors. If the growth cone is poised to respond to either the attractive or inhibitory Like so many fields of biology, progress in understandsignal, what determines the specific response? Bashaw ing the molecular mechanisms of axon guidance is proand Goodman (1999) hypothesize that the ectodomains ceeding at a frantic pace. During the last several years of these receptors determine ligand recognition, while a multitude of proteins have been identified that play the cytoplasmic domains specify the response. To test critical roles in guiding axons along their stereotypical this model, they generated chimeric receptors, fusing pathways (see Tessier-Lavigne and Goodman, 1996 for the ectodomain of Fra with the cytoplasmic domain of a general review). Attractive and repulsive signals have Robo (Fra-Robo) and the ectodomain of Robo with the been characterized, including the Ephrin, Netrin, Semacytoplasmic domain of Fra (Robo-Fra), and then exphorin, and the Slit protein families. Different classes of pressed these chimeric receptors in all neurons of the transmembrane receptors for these various guidance Drosophila embryonic CNS (Figure 1A). Bashaw and cues are also being identified and characterized. An Goodman observed that these chimeric receptors beunexpected theme is emerging for many of these guidhaved precisely as predicted by their hypothesis. Neuance signals: several of these protein families contain rons expressing high levels of the Fra-Robo chimeric members that act as bifunctional guidance cues, conferreceptor were repelled by Netrin-expressing midline ring both attractive and repulsive signals. cells leading to a lack of axons crossing the CNS midHow does a growth cone respond to a bifunctional line. This effect of the Fra-Robo receptor was Netrin guidance cue? Are responses mediated by the reperdependent. On the other hand, neurons expressing the toire of receptors on the growth cone surface, or are Robo-Fra chimeric receptor were attracted to the Slitthere other properties intrinsic to the growth cone that expressing midline cells, with many axons inappropridictate the response? Two papers in this issue of Cell ately crossing the CNS midline. For both chimeric recepfrom the Goodman lab (Bashaw and Goodman, 1999) tors, a variety of different genetic backgrounds were and from the Tessier-Lavigne and Poo labs (Hong et al., analyzed to demonstrate that these phenotypes were the 1999) address this question. They find that transmemresult of gain-of-function properties of the chimeric rebrane receptors determine whether a growth cone sees ceptor and not simply the result of dominant-negative a cue as attractive or repulsive, consistent with earlier effects. predictions. Moreover, the cytoplasmic domains of these receptors are the key effectors for initiating either an attractive or repulsive response. In addition, these receptors are surprisingly modular; ectodomains and cytoplasmic domains can be swapped without eliminating receptor function. Finally, Hong, Stein, and colleagues (Hong et al., 1999) demonstrate that formation of heteromeric receptor complexes can play a critical role in regulating the response of the growth cone to these complex bifunctional guidance cues. Cytoplasmic Domains of Guidance Receptors Are Key Effectors, Directing Either Attractive or Repulsive Responses The Drosophila CNS midline expresses both attractants and repellents that are recognized by distinct transmembrane receptors. Roundabout (Robo) is a receptor for the midline repellent signal Slit (Kidd et al., 1998, 1999). Frazzled (Fra), the Drosophila DCC ortholog, is the receptor for midline attractants of the Netrin family (Kolodziej et al., 1996 and references therein). The ectodomains of both Robo and Fra encode immunoglobulin domains and fibronectin type III repeats; the cytoplasmic domains of these proteins are unique and do