Hox Genes Are Involved in the Regional Specification of Neuronal Identity

Along the anteroposterior axis, the insect and vertebrate neuroectoderm is subdivided into compartment-like regions, each of which expresses a specific combination of conserved developmental control genes. In both animal groups, regions of the posterior brain and the nerve cord are specified by the expression and action of homeodomain transcription factors encoded by the Hox genes (see Figure 3). Hox genes were first identified in Drosophila and Hox gene orthologues have subsequently been found in all other bilaterian animals, including mammals. During embryonic development, these developmental control genes are involved in anteroposterior patterning of features such as the morphology of segments in Drosophila or the morphology of axial mesoderm derivatives in mammals. Hox genes generally respect the co-linearity rule: they are expressed along the body axis in the same order as they are found clustered on the chromosome. Their role in anteroposterior regionalization may have evolved early in metazoan history (Carroll, 1995).

In both invertebrates and vertebrates, Hox gene expression is especially prominent in the developing CNS, and the nervous system may be the most

Protocerebral Drosophila

otdi/Otx2 ™ lab/Hoxb-1 m Dfd/Hoxb-4 □ Ubx/Hoxb-7 m oia/UK2 ^ pb/Hoxb-2 □ Scr/Hoxb-5 □ abd-A/Hoxb-8

Figure 3 Conserved anteroposterior order of gene expression in embryonic brain development. Schematic diagram of Hox and otd/Otxgene expression patterns in the developing CNS of Drosophila and mouse. Expression domains are color-coded. (Top) Gene expression in embryonic stage 14 Drosophila CNS. Borders of the protocerebral (b1), deutocerebral (b2), tritocerebral (b3), mandibular (s1), maxillary (s2), labial (s3), and ventral nerve cord neuromeres are indicated by vertical lines. In contrast to the other Hox genes, pb is expressed only in small segmentally repeated groups of neuronal cells; this difference is indicated by a diagonally striped bar to denote the pb expression domain. (Bottom) Gene expression in embryonic day 9.5-12.5 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.

ancestral site of Hox gene action. In animal taxa investigated thus far, such as planarians (Orii et al.,

1999), nematodes (Kenyon et al., 1997), annelids (Kourakis et al., 1997; Irvine and Martindale,

2000), mollusks (Lee et al., 2003), arthropods (Hirth and Reichert, 1999; Hughes and Kaufman, 2002), urochordates (Ikuta et al., 2004), cephalo-chordates (Wada et al., 1999), hemichordates (Lowe et al., 2003), and vertebrates including zebra fish, chicken, mouse, and human (Lumsden and Krumlauf, 1996; Vieille-Grosjean et al., 1997; Carpenter, 2002; Moens and Prince, 2002), the Hox gene expression patterns in the developing CNS consist of an ordered set of domains that have a remarkably similar anteroposterior arrangement along the neuraxis.

The function of Hox genes in CNS development has been studied through loss- and gain-of-function experiments primarily in Drosophila, zebra fish, chicken, and mouse. In Drosophila, loss-of-function studies have shown that Hox genes are required for the specification of regionalized neuronal identity in the posterior brain (Hirth et al., 1998). Comparable results have been obtained through loss-of-function studies in vertebrates, where Hox genes are involved in specifying the rhombomeres of the developing hind-brain. For example, in the murine Hoxb1 mutant, rhombomere 4 (r4) is partially transformed to r2

identity (Studer et al., 1996), whereas in Hoxa1~'~; Hoxb1~'~ double mutants, a region corresponding to r4 is formed, but r4-specific neuronal markers fail to be activated, indicating the lack of neuronal identity of the remaining territory between r3 and r5 (Studer et al., 1998; Gavalas et al., 1998). This suggests that Hoxa1 and Hoxb1 act synergistically in the specification of r4 neuronal identity - a mode of action remarkably similar to that of their fly orthologue, labial, in specifying segmental neuronal identity during Drosophila brain development (Figure 4).

This evolutionarily conserved Hox gene action is underscored by experiments that show that even cis-regulatory regions driving the specific spatiotemporal expression of Hox genes appear to operate in a conserved manner in insects and vertebrates. Thus, the enhancer region of the human Hoxb4 gene, an orthologue of Drosophila Deformed, can function within Drosophila to activate gene expression in a Deformed-specific pattern, whereas the enhancer region of Drosophila Deformed activates Hoxb4-specific expression in the mouse hindbrain (Malicki et al., 1992). Similar results have been obtained for Hox1 orthologues (Popperl et al., 1995), suggesting that the expression, function, and regulation of Hox genes in the specification of segmental neuronal identity during CNS development may be an ancestral feature of this gene family.

Drosophila wt lab-

Mouse Hoxa1-/~; Hoxbl b2

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FasII

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Mouse Hoxa1-/~; Hoxbl

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