Vnc

Forebrain

Midbrain

Hindbrain

Spinal cord

Sensory vesicle

Neck

Visceral ganglion Tail nerve cord

| otd/Otx [": unpg/Gbx2 |_| Pax2/5/8 Hox1 orthologues

Figure 6 Tripartite organization of the (a) Drosophila, (b) mouse, and (c) ascidian brain, based on expression patterns of orthologous genes. The expression of otd/Otx2, unpg/Gbx2, Pax2/5/8, and Hox1 gene orthologues in the developing CNS of (a) stage 13/14 Drosophila embryo, (b) stage E10 mouse embryo, and (c) neurula ascidian embryo. In all cases, a Pax2/5/8-expressing domain is located between an anterior otd/Otx2 expressing region and a posterior Hox expressing region in the embryonic brain. Moreover, in Drosophila, as in mouse, a Pax2/5/8-expressing domain is positioned at the interface between the otd/Otx2 expression domain and a posteriorly abutting unplugged/Gbx2 expression domain. This otd/Otx2-unpg/Gbx2 interface displays similar developmental genetic features in both Drosophila and mouse. Reproduced from Hirth, F., Kammermeier, L., Frei, E., Walldorf, U., Noll, M., and Reichert, H. 2003. An urbilaterian origin of the tripartite brain: Developmental genetic insights from Drosophila. Development 130, 2365-2373, with permission from The Company of Biologists Ltd.

signaling molecules of the TGFb family such as Dpp, studied most extensively in Drosophila, and BMP-4, one of the vertebrate homologues of Dpp (De Robertis and Sasai, 1996). These proteins establish dorsoventral polarity in the insect embryo and in the vertebrate embryo. In both cases, they are restricted in their spatial activity by antagonistically acting extracellular signaling proteins. These antagonists are Sog in Drosophila and its homologue Chordin in vertebrates. The two groups of interacting signaling molecules, Dpp/BMP-4 and Sog/Chordin, act from opposing dorsoventral poles in both insects and vertebrate embryos (Holley et al., 1995). Remarkably, in Drosophila, Dpp exerts its activity on dorsal cells and Sog on ventral cells, whereas in vertebrates BMP-4 acts on ventral cells and Chordin activity is found in dorsal cells. In both cases, it is the region of the embryo that attains neurogenic potential and forms neuroectoderm in which Sog/Chordin is expressed and inhibits the action of invading Dpp/ BMP-4 signals.

Thus, despite the morphological differences between embryos of the two species, the Sog/Chordin gene is expressed on the side from which the CNS arises, whereas the dpp/Bmp-4 gene is expressed on the opposite side of the embryo where it promotes ectoderm formation. This functional conservation of the Sog/Chordin and the Dpp/BMP-4 morphogens suggests an evolutionarily conserved, homologous mechanism of dorsoventral patterning. This suggestion is further substantiated by experimental studies showing that injection of Chordin RNA (from Xenopus) promotes ventralization of cell fates in Drosophila embryos, including the formation of ectopic patches of CNS. Correspondingly, injection of sog RNA (from Drosophila) causes dorsal development in Xenopus, including the formation of notochord and CNS (Holley et al., 1995; Schmidt et al., 1995). Thus, the function of sog/ Chordin is reversed in insects and vertebrates; in both cases, injection of the gene product promotes the development of the side of the embryo that contains the CNS: dorsal in vertebrates, ventral in insects. This pervasive equivalence of gene structure and function points to an essential role of Sog/ Chordin and Dpp/BMP-4 in CNS induction/ specification in insects and vertebrates, irrespective of the location along the dorsoventral axis at which the CNS forms (Figure 7).

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