Extracellular Engrailed Participates in the Topographic Guidance of Retinal Axons In Vivo

Abstract

Engrailed transcription factors regulate the expression of guidance cues that pattern retinal axon terminals in the dorsal midbrain. They also act directly to guide axon growth in vitro. We show here that an extracellular En gradient exists in the tectum along the anterior-posterior axis. Neutralizing extracellular Engrailed in vivo with antibodies expressed in the tectum causes temporal axons to map aberrantly to the posterior tectum in chick and Xenopus. Furthermore, posterior membranes from wild-type tecta incubated with anti-Engrailed antibodies or posterior membranes from Engrailed-1 knockout mice exhibit diminished repulsive activity for temporal axons. Since EphrinAs play a major role in anterior-posterior mapping, we tested whether Engrailed cooperates with EphrinA5 in vitro. We find that Engrailed restores full repulsion to axons given subthreshold doses of EphrinA5. Collectively, our results indicate that extracellular Engrailed contributes to retinotectal mapping in vivo by modulating the sensitivity of growth cones to EphrinA.

Engrailed protects mouse midbrain dopaminergic neurons against mitochondrial complex I insults

“…Of particular relevance to this study is that Engrailed axon guidance activity requires its internalization and local protein translation 9,10 . The present work raises the possibility that…”

“…In this context, it is to note that Engrailed, although a transcription factor, also regulates mRNA translation 9,10 . This regulation, first observed in growth cones, probably engages the mTOR pathway as it is accompanied by the phosphorylation of eIF4E and 4E-BP1, two key regulators of protein translation 11 .…”

Comment faire beaucoup avec peu dans le système nerveux

“…On trouve des équivalents à cette boucle autocrine dans d'autres systèmes. Par exemple, la stimulation autocrine des récepteurs A3 en réponse à la sécrétion d'ATP permet en potentialisant les effets répulsifs de l'éphrine-A5 [5]. Chez l'amphibien, des gradients extracellulaires d'Engrailed repoussent in vitro les cônes de croissance temporaux et attirent les cônes de croissance nasaux.…”

“…Les homéoprotéines peuvent en effet réguler la traduction protéique via leur interaction avec le facteur d'initiation de la traduction EiF4E [7]. Les effets de la fraction extracellulaire d'Engrailed sont significatifs car l'administration in vivo d'anticorps dirigés contre cette protéine perturbe l'organisation des axones rétiniens [5]. …”

Postnatal signalling with homeoprotein transcription factors

“…En1/2 shows graded expression along the A-P axis and the in vivo expression of a single-chain antibody (aEn1/2-scfv) results in the invasion of the posterior tectum by temporal growth cones [14]. The effect of En1/2 on axon guidance in vitro is to attract and repel nasal and temporal growth cones, respectively [15].…”