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Fig. 1. Expression dynamics of selected genes during neural border and neural crest early development. (A) Expression of the some of the most commonly used markers for NB, NNE, NP and placodes. Upper row: Dorsal views of frog embryos at neural plate stage (stage 14, Nieuwkoop and Faber, 1994), stained for a selection of genes by whole-mount in situ hybridization: pax3, zic1 and msx1 are expressed at the NB, Six1 main expression delineates the preplacodal ectoderm (PPE) anteriorly, sox2 is expressed in the neural plate and epk marks the non neural ectoderm. Note the partial overlap between pax3 and sox2 in the lateral neural plate corresponding to the future dorsal part of the neural tube; and of Zic1 and Six1 in the PPE. Scale bar: 500 µm. Lower row: Cross-sections of neural plate stage 14 frog embryos stained by whole-mount in situ hybridization for the indicated genes. Pax3, zic1 and hes4 are expressed in the NB, sox2 is expressed in the neural plate with a partial overlap with pax3 in the lateral neural plate and epk is expressed in the non-neural ectoderm. Scale bar: 100 µm. (B) The comparison of the sequential temporal activation of selected genes in the NB/NC territory outlines the progressive specification of NB and NC in frog and chick embryos during gastrulation and neurulation. References for frog: AP2a (de Crozé et al., 2011), Id3 (Light et al., 2005, Kee and Bronner-Fraser, 2005), Pax3 (Bang et al., 1999, Monsoro-Burq et al., 2005), Gbx2 ((Li et al., 2009), Dlx5 (Luo et al., 2001a, Luo et al., 2001b; Steventon et al., 2012), Hes4 (Tsuji et al., 2003, Glavic et al., 2003), Zic1 (Mizuseki et al., 1998; Nakata et al., 1998), Snail1 (Aybar et al., 2003), c-myc ((Bellmeyer et al., 2003), Zic5 (Nakata et al., 2000), Sox9 (Spokony et al., 2002), Ednra (Bonano et al., 2008), Snail2 (Mayor et al., 1995; Aybar et al., 2003), Foxd3 (Sasai et al., 2001), Sox10 (Aoki et al., 2003; Honoré et al., 2003), Anosmin-1 (Bae et al., 2018), Tfap2e (Hong et al., 2014). References for chick: Pax7 (Basch et al., 2006); c-myc (Khudyakov et al., 2009; Keruoso et al., 2016); c-myb (Betancur et al., 2014); DNMT3a (Hu et al., 2012); Snail2 (Nieto et al., 1994; Endo et al., 2002); NSD3 (Jacques-Fricke et al., 2014); Foxd3 (Kos et al., 2001); Msx1 (Khudyakov et al., 2009); LSox5 (Perez-Alcala et al., 2004); Ets1 (Barembaum and Bronner, 2013); Sox10 (Cheng et al., 2000).
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Fig. 2. The Hourglass model of NC induction: upstream and downstream of Pax3/Zic1. (A) General presentation of the "Hourglass model" for NB/NC-GRN, divided into a neural border module upstream of the activation of the two essential TFs Pax3 and Zic1, and a downstream module, describing Pax3 and Zic1 targets in subsequent NC induction. (B) Through a combination of Wnt, FGF and modulated BMP signals, NB-TFs are activated and mutually enhance each other's expression, creating a feed-forward NB stabilization loop, culminating with the robust and balanced activation of Pax3 and Zic1. (C) In turn, the balanced expression of Pax3 and Zic1 is necessary and sufficient to trigger all downstream aspects of NC development. The Pax3/Zic1-dependent GRN presented here has been validated in animal caps assays in vitro and frog whole embryos in vivo. The main regulations are shown, including the direct activation of the EMT-TFs snail2 and twist1 (ets1, also direct target EMT-TF is not shown). Direct regulations are shown with solid lines, other regulatory connections with dashed lines. References: Bonano et al. (2008); Marchal et al. (2009); Li et al. (2009); Gutkovich et al., 2010; Bae et al. (2014); Plouhinec et al. (2014).
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