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Engrailed Homeoproteins in Visual System Development

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Engrailed Homeoproteins in Visual System Development Cell. Mol. Life Sci. (2015) 72:1433–1445 DOI 10.1007/s00018-014-1776-z Cellular and Molecular Life Sciences REVIEW Engrailed homeoproteins in visual system development Andrea Wizenmann • Olivier Stettler • Kenneth L. Moya Received: 28 July 2014 / Revised: 31 October 2014 / Accepted: 6 November 2014 / Published online: 29 November 2014 Ó The Author(s) 2014. This article is published with open access at Springerlink.com Abstract Engrailed is a homeoprotein transcription Keywords Visual system Á Retina Á Tectum Á factor. This family of transcription factors is characterized Sensory map Á Homeoprotein Á Engrailed by their DNA-binding homeodomain and some members, including Engrailed, can transfer between cells and reg- ulate protein translation in addition to gene transcription. Introduction Engrailed is intimately involved in the development of the vertebrate visual system. Early expression of Engrailed in Since the discovery of homeobox genes [1, 2] there has dorsal mesencephalon contributes to the development and been accumulating evidence from all multi-cellular organization of a visual structure, the optic tectum/supe- organisms that these genes play key roles in determining rior colliculus. This structure is an important target for positional information. These genes encode homeoprotein retinal ganglion cell axons that carry visual information transcription factors that regulate the expression of down- from the retina. Engrailed regulates the expression of stream genes necessary at all developmental stages, Ephrin axon guidance cues in the tectum/superior col- including lineage determination, cell migration, cell dif- liculus. More recently it has been reported that Engrailed ferentiation, and tissue formation. Some homeoproteins are itself acts as an axon guidance cue in synergy with the also able to regulate protein translation and cell-to-cell Ephrin system and is proposed to enhance retinal topo- signaling. The proteins of the Engrailed family can exert all graphic precision. three functions, regulate gene transcription and protein translation, and act in an extracellular signaling pathway. All three of these functions of Engrailed are put into play for the correct development of the visual system in vertebrates. A. Wizenmann (&) Department of Anatomy, Institute of Clinical Anatomy and Cell Analysis, University of Tu¨bingen, O¨ sterbergstrasse 3, 72074 Non-cell autonomous homeoprotein activity and visual Tu¨bingen, Germany system development e-mail: [email protected] O. Stettler The non-cell autonomous developmental function of ho- Laboratoire CRRET EAC 7149, Universite´ Paris-Est Cre´teil, 61, meoproteins has only recently been deciphered and opens an Av. du Ge´ne´ral de Gaulle, 94010 Cre´teil Cedex, France entirely new view on developmental processes. Pax 6 is nec- essary for eye development in many species [3–6] and this was K. L. Moya (&) Colle`ge de France, Center for Interdisciplinary Research in attributed to its cell autonomous activity. However, when the Biology, UMR CNRS 7241/INSERM U1050, 11 place Marcelin intercellular passage of Pax6 is disrupted in zebrafish Berthelot, 75005 Paris, France embryos, fish develop dissymmetric eyes, one eye or no eye e-mail: [email protected] phenotypes [7]. The homeoprotein Otx2 is expressed in the K. L. Moya retina and is important for retinal ganglion cell (RGC) prenatal Labex Memolife, PSL Research University, Paris, France specification and, after birth, for the maintenance of cone 123 1434 A. Wizenmann et al. photoreceptors, bipolar cells and RGCs [8]. Since postnatal different organisms (for review see: [29]). Vertebrate RGCs do not express Otx2, this dependence on Otx2 for homologues were discovered in chick, mice, frogs and fish maintenance or neuroprotection [9] is another example of [28, 30–32]. Vertebrates in general have 2–3 Engrailed non-cell autonomous homeoprotein activity. genes and in most species they confer specific identity to Beyond the retina, Otx2 can be transferred to the visual defined areas and neurons. cortex from external sources and blocking its transfer and Engrailed proteins contain highly conserved homeodo- accumulation in parvalbumin cells within layers III and IV mains (Fig. 1), domains involved in active repression of of visual cortex regulates the opening, closure or reopening transcription [33], and domains that bind important co-fac- (in the adult) of a critical period for the plasticity of the tors like Groucho and Extradenticle (Exd)/Pbx [34, 35]. The visual cortex [10–12]. phosphorylation of specific residues increases DNA binding Engrailed proteins now have a twofold role for the [36]. With Exd as a cofactor Drosophila Engrailed, normally development of the subcortical visual connections: first, a repressor, can also act as transcriptional activator in vivo Engrailed transcriptional activity is important for the for- [37]. Like other homeodomain proteins Engrailed protein mation of subcortical visual structures in the brain; second also acts as translational regulator and interacts with elF4E its protein translation and cell–cell signaling properties [38–40]. Surprisingly, Engrailed also possesses domains that guide retinal axons in the formation of visual maps. allow the protein to be secreted and internalized [41]. That Engrailed transcription factors contain these domains and Engrailed transfer between cells has been reported for some time but only recently has the physiological significance of this been The Drosophila gene Engrailed was first identified in 1929 fully appreciated (for reviews see [12], [42]). as an autosomal recessive gene [13]. Since the mutant possessed a dent in the scutellum Eker called it Engrailed The vertebrate visual system and topographic maps after ‘engraile´’ a heraldic term from middle-age French meaning ‘dented by hail’. Engrailed turned out to be a key An essential aspect of nervous system development is the selector gene that is involved in the development of pos- establishment of precise functional neuronal connections in terior compartments of appendages and segments [14–16] the brain. Locally, these connections can form specific and the nervous system [17, 18] during Drosophila devel- networks (i.e. a cerebral maps) that topographically opment. Since then, one or more Engrailed proteins have reproduce the spatial organization of the peripheral sensory been described in many metazoans from echinoderms [19], receptors. The development of precise projections implies nematodes [20], annelids [21], brachiopods [22], platyhel- that growing axons, (1) carry an identity of their place of minthes [23], molluscs [24], cephalochordates [25], origin; (2) follow the correct pathway towards their target; onychophorans [26] priapulids [27] and in vertebrates [28]. and (3) recognize a local ‘‘stop signal’’ to synapse on their Duplications generated several Engrailed paralogues in proper target cells. The overall process requires in addition, Secretion Motif Internalisation part of NES motive (Penetrin) Phosphorylation sequence EH1 EH2 EH3 EH4 EH5 N C elF4E Groucho PBX Homeodomain Transcriptional binding binding binding respression domain domain domains Fig. 1 Functional domains of Engrailed proteins. En1/2 contain a phosphorylation appears to regulate En1/2s association with mem- classic homeodomain. Within the homeodomain, Engrailed proteins brane fractions enriched in cholesterol and glycosphingolipids. NES have a secretion and an internalization motif (Penetratin). At the is the nuclear transport signal within the homebox. Modified from N-terminal region a binding site for elf4E and a phosphorylation site Morgan 2006. See text and Morgan 2006 for references were identified. Elf4E initiates protein translation and the 123 Engrailed homeoproteins 1435 superior colliculus (SC) in mammals. The retina is repre- sented topographically in the oTe/SC such that axons from temporal retina project to the anterior oTe/SC, and axons from nasal retina project to the posterior oTe/SC. The dorso-ventral axis of the retina is represented along the latero-medial axis of the tectum (see Fig. 2). One early theory for how this precise map is established during development was suggested by Sperry more than 50 years ago as the ‘chemoaffinity hypothesis’. Based on eye rotation experiments in amphibians he postulated two orthogonal ‘cytochemical’ gradients in the retina, so as to impose positional identity onto each retinal ganglion cell ‘in a kind of chemical code’ along the naso-temporal and dorso-ventral axis of the eye [44]. These gradients would then be matched with complementary gradients in the tectal Fig. 2 Topographical organization of the retinotectal system and the target field of the retinal projection (Fig. 2). Mathematical graded expression of guidance cues and receptors. Anterior tectum receives the input from temporal axons, posterior tectum receives models for the arrangement of these gradients, and the input from nasal axons. Within the tectum the earliest graded capacity of growth cones to correctly navigate along these expression is that of En1/2, which shows a high expression in the gradients were proposed by Gierer [45–47]. Subsequently, posterior and a low expression in the anterior tectum. Later different numerous studies in vivo and in vitro provided evidence for Eph As and Ephrins—the member depends on the species—are expressed in counter gradients along the tempero-nasal axis of the the existence of positional cues along the rostrocaudal and retina and the anterior–posterior axis of the tectum.
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