Pax transcription factors are involved in a variety of developmental processes in bilaterians, including eye development, a role typically assigned to Pax-6. Although no true Pax-6 gene has been found in nonbilateral animals, some jellyfish have eyes with complex structures. In the cubozoan jellyfish Tripedalia , Pax-B , an ortholog of vertebrate Pax-2/5 / 8 , had been proposed as a regulator of eye development. Here we have isolated three Pax genes ( Pax-A , Pax-B , and Pax-E ) from Cladonema radiatum , a hydrozoan jellyfish with elaborate eyes. Cladonema Pax-A is strongly expressed in the retina, whereas Pax-B and Pax-E are highly expressed in the manubrium, the feeding and reproductive organ. Misexpression of Cladonema Pax-A induces ectopic eyes in Drosophila imaginal discs, whereas Pax-B and Pax-E do not. Furthermore, Cladonema Pax-A paired domain protein directly binds to the 5′ upstream region of eye-specific Cladonema opsin genes, whereas Pax-B does not. Our data suggest that Pax-A , but not Pax-B or Pax-E , is involved in eye development and/or maintenance in Cladonema . Phylogenetic analysis indicates that Pax-6 , Pax-B , and Pax-A belong to different Pax subfamilies, which diverged at the latest before the Cnidaria–Bilateria separation. We argue that our data, showing the involvement of Pax genes in hydrozoan eye development as in bilaterians, supports the monophyletic evolutionary origin of all animal eyes. We then propose that during the early evolution of animals, distinct classes of Pax genes, which may have played redundant roles at that time, were flexibly deployed for eye development in different animal lineages.
BackgroundCrossveinless-2 (CV2) is an extracellular BMP modulator protein of the Chordin family, which can either enhance or inhibit BMP activity. CV2 binds to BMP2 via subdomain 1 of the first of its five N-terminal von Willebrand factor type C domains (VWC1). Previous studies showed that this BMP binding is required for the anti-, but not for the pro-BMP effect of CV2. More recently, it was shown that CV2 can also bind to the BMP inhibitor Chordin. However, it remained unclear which domains mediate this binding, and whether it accounts for an anti- or pro-BMP effect.Principal FindingsHere we report that a composite interface of CV2 consisting of subdomain 2 of VWC1 and of VWC2-4, which are dispensable for BMP binding, binds to the VWC2 domain of Chordin. Functional data obtained in zebrafish embryos indicate that this binding of Chordin is required for CV2's pro-BMP effect, which actually is an anti-Chordin effect and, at least to a large extent, independent of Tolloid-mediated Chordin degradation. We further demonstrate that CV2 mutant versions that per se are incapable of BMP binding can attenuate the Chordin/BMP interaction.ConclusionsWe have physically dissected the anti- and pro-BMP effects of CV2. Its anti-BMP effect is obtained by binding to BMP via subdomain1 of the VWC1 domain, a binding that occurs in competition with Chordin. In contrast, its pro-BMP effect is achieved by direct binding to Chordin via subdomain 2 of VWC1 and VWC2-4. This binding seems to induce conformational changes within the Chordin protein that weaken Chordin's affinity to BMP. We propose that in ternary Chordin-CV2-BMP complexes, both BMP and Chordin are directly associated with CV2, whereas Chordin is pushed away from BMP, ensuring that BMPs can be more easily delivered to their receptors.
Eyes absent (Eya) is a member of the Retinal Determination Gene Network (RDGN), a set of genes responsible for eye specification in Drosophila. Eya is a dual function protein, working as a transcription factor in the nucleus and as a tyrosine phosphatase in the cytoplasm. It had been shown that Pax and Six family genes, main components of the RDGN, are present in the hydrozoan Cladonema radiatum and that they are expressed in the eye. However, nothing had been known about the Eya family in hydrozoan jellyfish. Here we report the presence of an Eya homologue (CrEya) in Cladonema. Real-time PCR analysis and in situ hybridization showed that CrEya is expressed in the eye. Furthermore, the comprehensive survey of eukaryote genomes revealed that the acquisition of the N-terminal transactivation domain, including the EYA Domain 2 and its adjacent sequence shared by all eumetazoans, happened early in evolution, before the separation of Cnidaria and Bilateria. Our results uncover the evolution of the two domains and show a conservation of the expression pattern of the Eya gene between Cnidaria and Bilateria, which, together with previous data, supports the hypothesis of the monophyletic origin of metazoans eyes. We additionally show that CrEya is also expressed in the oocytes, where two other members of the RDGN, CrPaxB, and Six4/5-Cr, are known to be expressed. These data suggest that several members of the RDGN have begun to be localized also into the different context of egg development early in the course of metazoan evolution.
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