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  • In mouse embryos both the developing retina and

    2018-10-20

    In mouse embryos, both the developing retina and the ventral hypothalamus show strong Rax expression (Ikeda et al., 2005; Wataya et al., 2008; Wilson and Houart, 2004). Consistent with previous studies (Ikeda et al., 2005; Wataya et al., 2008), we confirmed that SHH agonists upregulated Rax in mESCs but in the context of ventral hypothalamic specification, because Rax-expressing purchase FG4592 were positive for NKX2.1 and negative for PAX6. Upon terminal differentiation, these cultures generated GAD65-positive neurons. Side-by-side comparison of Activin and SAG treatments confirmed that the effects of these molecules were clearly distinguishable. Activin, but not SAG, supported specification of Rax-PAX6-positive retinal progenitors, which were endowed with transcriptomic profiles clustering with those of embryonic eye tissue and were capable of undertaking retinal neuron differentiation in long-term cultures. Activin/Nodal signaling controls early vertebrate development at multiple levels, and it is difficult to distinguish direct roles in eye development from indirect effects. Forebrain and eye formation are affected in fish and mouse mutants with defective Activin/Nodal signaling (Lu and Robertson, 2004; Varlet et al., 1997; Wilson and Houart, 2004), but these effects are likely due to the disruption of mesendodermal signaling centers required for rostral neuroectoderm formation (Wilson and Houart, 2004). Excessive Activin/Nodal signaling, however, can repress anterior neural fates by maintaining pluripotency and/or promoting mesendoderm differentiation within the ectoderm (Thisse et al., 2000; Vallier et al., 2004). Anterior neural induction occurs prematurely in the epiblast of Nodal mouse mutants (Camus et al., 2006), but although telencephalic genes are upregulated in Nodal-deficient anterior neuroectoderm, eye field markers (Six3 and Pax6) are not properly expressed (Camus et al., 2006). Furthermore, during eye morphogenesis, eye field cells migrating laterally to form the optic vesicles become exposed to Activin-like signals released by extraocular tissues. Although these signals are involved in retinal pigment epithelium and anterior eye segment specification (Fuhrmann et al., 2000; Ittner et al., 2005), they might also support retinal progenitor identity. Highlighting the complex functions of Activin/Nodal signaling in eye development, recent studies in Xenopus found opposite effects of Nodal signaling inhibition on the specification of retinal identity using different experimental assays (Messina et al., 2015; Wong et al., 2015). Clearly, the roles of Activin/Nodal signaling in eye formation are much more difficult to dissect in vivo than they are in vitro, and further investigations in animal model organisms are warranted. The results described in this and previous studies using ESC in vitro systems (Bertacchi et al., 2013, 2015; Lupo et al., 2013, 2014) lead to a model of the role of the Activin/Nodal pathway in the specification of retinal identity (Figure 7). In this model, downregulation of Activin/Nodal signaling in pluripotent cells leads to the emergence of early anterior neural progenitors, which can acquire rostral forebrain fates (corresponding to progenitors of the secondary prosencephalon in vivo) or caudal forebrain fates (corresponding to progenitors of the diencephalic/mesencephalic regions in vivo) depending on the levels of Wnt/β-catenin signaling, as previously described (Lupo et al., 2014 and references therein). Without further signaling, primitive rostral forebrain progenitors spontaneously evolve toward a default cortical identity (Bertacchi et al., 2013; Lupo et al., 2014), whereas they can be steered to retinal fates under the influence of Activin. As in previous studies (Ikeda et al., 2005; Wataya et al., 2008), SHH signaling instead promotes ventral hypothalamic fates. Although more work is needed to address the function of Activin/Nodal signals during early eye development in vivo, this model provides a framework for future studies aimed at clarifying the mechanisms of eye field formation and producing retinal progenitors for basic research or therapy.