Xenopus retinal neurons project to the optic tectum to form a topographic map of the retina; neurons from the nasal retina terminate in the caudal tectum, whereas neurons from the temporal retina project to the rostral tectum. The homeodomain transcription factor Engrailed-2 (En-2), which is expressed in a caudal-to-rostral gradient, is believed to play a role in establishing gradients of ligands and receptors that underlie formation of such maps through its effects on gene transcription. Noting that En-2 possesses domains implicated in secretion and internalization, Brunet et al. investigated the possibility that it played a more direct role in establishment of the topographic map. When exposed to an En-2 gradient in vitro, axons from the nasal retina were attracted to En-2, whereas axons from the temporal retina were repelled. Fluorescently labeled En-2 accumulated in the growth cones and neurite shafts of retinal neurons; a mutant form that did not enter growth cones failed to elicit turning in nasal axons. Turning was initiated more rapidly than would be expected for transcriptional effects and occurred in growth cones transected from their cell body. Internalized En-2 promoted protein synthesis in isolated growth cones, and both pharmacological and mutational analysis indicated that En-2 stimulated turning responses through effects on translation. Consistent with the notion that it activates translation, internalized En-2 stimulated the phosphorylation of eukaryotic initiation factor 4E (eIF4E) and eIF4E-binding protein-1. Thus, the authors propose that, in addition to its role as a transcription factor, En-2 may play a direct role in formation of the topographic map.
I. Brunet, C. Weinl, M. Piper, A. Trembleau, M. Volvitch, W. Harris, A. Prochiantz, C. Holt, The transcription factor Engrailed-2 guides retinal axons. Nature 438, 94-98 (2005). [PubMed]