The transcription factor Engrailed-2 guides retinal axons

Abstract

Engrailed-2 (En-2), a homeodomain transcription factor, is expressed in a caudal-to-rostral gradient in the developing midbrain, where it has an instructive role in patterning the optic tectum--the target of topographic retinal input. In addition to its well-known role in regulating gene expression through its DNA-binding domain, En-2 may also have a role in cell-cell communication, as suggested by the presence of other domains involved in nuclear export, secretion and internalization. Consistent with this possibility, here we report that an external gradient of En-2 protein strongly repels growth cones of Xenopus axons originating from the temporal retina and, conversely, attracts nasal axons. Fluorescently tagged En-2 accumulates inside growth cones within minutes of exposure, and a mutant form of the protein that cannot enter cells fails to elicit axon turning. Once internalized, En-2 stimulates the rapid phosphorylation of proteins involved in translation initiation and triggers the local synthesis of new proteins. Furthermore, the turning responses of both nasal and temporal growth cones in the presence of En-2 are blocked by inhibitors of protein synthesis. The differential guidance of nasal and temporal axons reported here suggests that En-2 may participate directly in topographic map formation in the vertebrate visual system.

Ephrin-As and Patterned Retinal Activity Act Together in the Development of Topographic Maps in the Primary Visual System

“…Alternatively, in a mechanism similar to that proposed to explain how spontaneous spinal cord activity regulates motor neuron pathfinding decisions (Hanson and Landmesser, 2004), retinal activity may regulate the function or expression of non-ephrin-A axon guidance molecules that provide N-T mapping information. For example, if N-T topography is governed by two sets of graded repellent molecules (for instance, ephrin-As and engrailed) (Brunet et al, 2005) and the expression or the release of engrailed is regulated by neural activity, then the combined removal of ephrin-As and ␤2 would eliminate all mapping information.…”

Evidence for Developmentally Regulated Local Translation of Odorant Receptor mRNAs in the Axons of Olfactory Sensory Neurons

“…For example, in embryonic rat dorsal root ganglia neurons, Semaphorin 3A-induced local translation of RhoA mRNA is necessary and sufficient for growth cone collapse (Wu et al, 2005). In various neuronal preparations, cue-dependent local translation of mRNAs in growth cones seems to be necessary for the attractive or repulsive actions of guidance cues (Campbell and Holt, 2001;Brunet et al, 2005;Leung et al, 2006;Yao et al, 2006), although it may not be required in certain circumstances (Roche et al, 2009). Remarkably, local translation of the ephrin receptor EphA2 is activated in commissural neurons growth cones as they cross the midline, a phenomenon that is likely involved in their change in responsiveness to guidance cues at this intermediate target (Brittis et al, 2002).…”

Asymmetric redistribution of GABA receptors during GABA gradient sensing by nerve growth cones analyzed by single quantum dot imaging

“…Axonal navigation in external gradients has been described for different guidance signals, including neurotrophins (4), netrins (5), semaphorins (6), homeoproteins (7), and neurotransmitters (8). The end tip of the axon, the growth cone (GC), is a highly efficient gradient sensor, which can detect concentration difference across its spatial extent below a couple of percents (5,9).…”