Cephalic Gap Genes in Regionalization of the Anterior Brain The otdOtx Genes

In none of the animal species investigated to date are Hox genes expressed in the most anterior regions of the developing CNS. This suggests that the developing CNS is subdivided into a posterior Hox region and a more anterior non-Hox region. In both invertebrates and vertebrates, the non-Hox region of the anterior brain is characterized by the expression and action of the cephalic gap genes tailless (tll)/Tlx, orthodenticle (otd)/Otx, and empty spiracles (ems)/Emx (Arendt and NUbler-Jung, 1996). The most prominent example of cephalic gap genes acting in brain development is that of the otd/Otx genes. As is the case of the Hox genes, the CNS-specific expression of the otd/Otx genes is conserved throughout most of the animal kingdom.

otd/Otx genes are expressed in the anterior part of the developing nervous system in planarians (Umesono et al., 1999), nematodes (Lanjuin et al., 2003), annelids (Bruce and Shankland, 1998; Arendt et al., 2001), mollusks (Nederbragt et al., 2002), arthropods (Hirth and Reichert, 1999; Schroder, 2003), urochordates (Wada et al., 1998), cephalo-chordates (Tomsa and Langeland, 1999), hemichordates (Lowe et al., 2003), and vertebrates (Acampora et al., 2001b; Schilling and Knight, 2001).

Functional studies, carried out primarily in Drosophila and mouse, have shown that otd/Otx gene activity is essential for the formation of the anterior neuroectoderm. In Drosophila, otd is expressed in the developing brain throughout most of the protocerebrum and adjacent deutocerebrum. In otd mutants, the protocerebrum is deleted due to defective neuroectoderm specification and the subsequent failure of neuroblast formation (Hirth et al., 1995; Younossi-Hartenstein et al., 1997). Loss-of-function analyses for Otx genes carried out in the mouse show that these genes are also critically required at different stages in the development of the anterior brain. Otx2 null mice are early embryonic lethal and lack the rostral neuroectoderm that is normally fated to become the forebrain, midbrain, and rostral hindbrain due to an impairment in early specification of the anterior neuroectoderm by the visceral endoderm. Otx1 null mice show spontaneous epileptic seizures and abnormalities affecting the telencephalic dorsal cortex and the mesencepha-lon, as well as parts of the cerebellum and certain components of the acoustic and visual sense organs (Acampora et al., 2001b).

These essential roles of the otd/Otx genes in anterior brain development of insects and vertebrates suggest an evolutionary conservation of otd/Otx genes in embryonic brain development that extends beyond gene structure to patterned expression and function (Figure 5). A direct experimental demonstration of this functional conservation has been carried out in genetic cross-phylum rescue experiments. Thus, human Otx transgenes have been expressed in Drosophila otd mutants (Leuzinger et al., 1998) and, conversely, the murine Otx1 and b1 b2 b3

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Ventral nerve cord

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Rhombomeres 12 3 4 5 6 7 8

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Ventral nerve cord

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Figure 5 Conserved expression and function of the otd/Otx2 genes in embryonic brain development. Schematic diagram of otd and Otx2 gene expression patterns and otd and Otx2 mutant phenotypes in the developing CNS of Drosophila and mouse. (Top) otd gene expression in the wild type (wt) and brain phenotype of otd null mutant in embryonic stage 14 Drosophila CNS. Borders of the protocerebral (b1), deutocerebral (b2), tritocerebral (b3), mandibular (s1), maxillary (s2), labial (s3), and some of the ventral nerve cord neuromeres are indicated by vertical lines. (Bottom) Otx2 gene expression in the wild type (wt) and brain phenotype of Otx2 homozygous null mutant in embryonic day 12.5 mouse CNS. Borders of the telencephalon (T), diencephalon (D), mesencephalon (M),and rhombomeres are indicated by vertical lines. Reproduced from Hirth, F. and Reichert, H. 1999. Conserved genetic programs in insect and mammalian brain development. Bioessays 21, 677-684, with permission from John Wiley & Sons, Inc.

Otx2 genes have been replaced with the Drosophila otd gene in the mouse (Acampora et al., 1998a, 2001b). Intriguingly, despite the obvious anatomical differences between mammalian and Drosophila brains, the human Otx1 and Otx2 genes complemented the brain defects in otd mutant Drosophila and, similarly, the //" Drosophila otd gene was able to rescue most of the CNS defects of Otx1 and Otx2~ mutant mice (Acampora et al., 1998a, 1998b, 2001a; Leuzinger et al., 1998).

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