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Abstract
Homeoproteins of the Engrailed family are involved in the patterning of mesencephalic boundaries through a mechanism classically ascribed to their transcriptional functions. In light of recent reports on the paracrine activity of homeoproteins, including Engrailed, we asked whether Engrailed intercellular transfer was also involved in brain patterning and boundary formation. Using time-controlled activation of Engrailed combined with tools that block its transfer, we show that the positioning of the diencephalic-mesencephalic boundary (DMB) requires Engrailed paracrine activity. Both zebrafish Eng2a and Eng2b are competent for intercellular transfer in vivo, but only extracellular endogenous Eng2b, and not Eng2a, participates in DMB positioning. In addition, disruption of the Pbx-interacting motif in Engrailed, known to strongly reduce the gain-of-function phenotype, also downregulates Engrailed transfer, thus revealing an unsuspected participation of the Pbx interaction domain in this pathway.
Highlights
Engrailed proteins form a subclass of the homeoprotein transcription factor family that play multiple roles in the patterning of metazoan embryos
We first used an orthologous chicken Engrailed 2 (En2), similar to the zebrafish Engrailed 2 proteins (Eng2a and Eng2b), because its photoactivation has been well characterised in a previous study (Fournier et al, 2013)
In this study, we show that ectopic En2 modifies brain patterning only when activated between dome and 1-2 somite stages, corroborating and refining the initial experiments performed with Eng2a (Ando et al, 2001) or Eng2b (Scholpp et al, 2003)
Summary
Engrailed proteins form a subclass of the homeoprotein transcription factor family that play multiple roles in the patterning of metazoan embryos. Conserved domains in Engrailed proteins include the homeodomain (HD, the DNA-binding motif that defines homeoproteins; Gehring et al, 1994) and a hexapeptide shared with many homeoproteins, which is responsible for the interaction with cofactors of the PBC (exd and Pbx) family (Peltenburg and Murre, 1996) The transfer property primarily resides within the HD itself, which contains two distinct peptide motifs involved in secretion and internalisation (Derossi et al, 1994; Dupont et al, 2007) This unusual behaviour for transcription factors endows several homeoproteins (which by definition all contain the HD motif) with paracrine signalling properties, as reported for Engrailed in fly crossvein development (Layalle et al, 2011) or vertebrate axonal retino-tectal projection (Brunet et al, 2005; Wizenmann et al, 2009), as well as for other homeoproteins in neuronal plasticity (Sugiyama et al, 2008; Beurdeley et al, 2012; Spatazza et al, 2013b), eye field development (Lesaffre et al, 2007), oligodendrocyte migration (Di Lullo et al, 2011) or cell proliferation (Zhou et al, 2012)
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