Fig. 3. Retinotectal axon guidance requires the graded expression of receptors and ligands, as well as a possible paracrine role for a transcription factor. (A) Retinal ganglion cells (RGCs) project axons in an orderly manner from the retina to the tectum in order to ensure that an image (red arrow) perceived in the retina is precisely represented in the tectum. Axons from the temporal (T) region of the retina project to the anterior (A) region of the tectum, whereas axons from the nasal (N) region extend to posterior (P) tectum. Formation of this precise retinotopic map relies on the graded activity of several molecules, including the EphA receptor tyrosine kinases, their ephrin ligands and the transcription factor En-2. RGCs with high EphA-receptor levels are repelled by ephrin and navigate to the tectal region that has lower levels of the ligand. RGCs with lower receptor levels can extend into regions of the tectum with higher levels of ephrin. En-2 levels in the tectum also influence map formation, with temporal axons avoiding posterior regions of the tectum that have higher levels of En-2. (B) En-2 can act as a soluble molecule to differentially influence the outgrowth of temporal and nasal RGCs. In an in vitro turning assay, nasal axons are attracted to a source of En-2(+), whereas temporal axons are repelled by high levels of En-2. (C) En-2 enters the temporal and nasal growth cones where it stimulates eIF4E and eIF4E-BP phosphorylation. Phosphorylated eIF4E is believed to trigger the translation of different proteins in nasal and temporal axons to generate an attractive or repulsive response, respectively.