AMIGOs line developing and mature fiber tracts.

Amphoterin, a heparin-binding protein isolated from perinatal rat brain, has the intriguing ability to promote neurite outgrowth, but its mechanism of action remains unknown. On page 963, Kuja-Panula et al. use mRNA differential display to identify an amphoterin-induced gene called AMIGO, leading to the discovery of a small family of similar proteins that may mediate extracellular interactions in both neurite outgrowth and other types of cell movement.

After cloning the AMIGO gene, the authors identified two related genes, AMIGO-2 and AMIGO-3, by sequence homology. All three appear to encode type I transmembrane receptors, each with six leucine-rich repeats (LRRs) and one immunoglobulin-like domain. AMIGO is expressed at high levels in the nervous system, while AMIGO-2 and AMIGO-3 are distributed in a variety of tissues. Chimeric AMIGO bound to a surface can act as a substrate for neurite outgrowth, apparently through homophilic interactions with AMIGO on the neuron. The three AMIGOs are also heterophilic, interacting with each other.

AMIGO expression peaks at two points in mammalian development, corresponding to the periods when myelination and the perinatal growth of axonal connections occur. During the perinatal peak, homophilic binding by AMIGO may direct fasciculation, forging interactions between new axons and the pioneer axons that act as guides for growth. Continued expression of AMIGO into adulthood suggests that it may help during the healing of fiber tracts.

Mechanistic similarities between growth cone migration and tumor cell invasion, and the broad tissue distribution of the new protein family, suggest that AMIGOs may be general purpose directors of cell migration. The new work also identifies a potential function for the LRR domain, a structural motif that is widely distributed among animal proteins but has remained largely uncharacterized. In the new protein family, LRRs may mediate ligand binding. The authors are now looking for additional proteins that interact with the AMIGOs, and are generating mice lacking each of the newly discovered genes. ▪