Conserved genes conserved biochemical functions

The conservation of the genetic toolkit for developmental genes extends beyond primary protein sequences. Even though these genes are used in animals with radically different modes of development, in vivo comparisons of protein activity have revealed similarities in biochemical function between orthologous proteins. In particular, studies have demonstrated the ability of genes from evolutionarily distant species to recapitulate the activity of orthologous genes during development.

For example, overexpression of vertebrate Hoxbl and Hoxb4 genes in Drosophila generates phenotypes that resemble the effects of overexpression of the Drosophila labial and Dfd genes, respectively. The sequence similarity between vertebrate Hox proteins and their arthropod orthologs is limited to the homeodomain and two other short peptides, and these sequences appear to be sufficient for most Hox protein functions (with some exceptions, as noted in the previous section). As a general rule for Hox genes and many other toolkit genes, protein sequence conservation often reflects conservation of biochemical functions.

The functional conservation of transcription factors such as the Hox proteins probably derives from the constraints imposed by their regulation of potentially very large numbers of target genes. It may be very difficult for the sequence of a homeodomain to change, as a modification may affect its DNA-binding specificity and therefore alter the ability of the protein to properly regulate all of its target genes. A modification to a Hox protein that simultaneously disrupts multiple Hox-regulated networks would be catastrophic to development. Similarly, signaling pathways are used in a variety of tissues and at different stages of development; hence, a change in the ability of a ligand to interact with its receptor or a change in the interactions between other pathway components could have wide-ranging, dire consequences. For this reason, the evolution of toolkit proteins is constrained in order to maintain long-established ancestral biochemical functions.

Similarities in the biochemical functions of orthologs do not necessarily indicate that these genes are used for the same developmental function in their respective organisms, however. This point is most readily apparent for signaling proteins. Conserved biochemical functionality for a signaling protein simply requires conservation of its ability to bind to a receptor and trigger an intracellular signaling cascade. For example, in vertebrates and in fruit flies, the Hedgehog protein binds to the Patched receptor protein, thereby activiating the Cubitus interruptus/Gli transcription factor (see Chapter 2 and Table 2.2). Nevertheless, the developmental outcome is different in each organism. In the vertebrate neural tube, a gradient of Hedgehog signaling generates different neuronal identities; in Drosophila, this pathway is used during segmentation and later in imaginal discs to pattern a variety of insect structures. Similarly, orthologous transcription factors may share the same DNA binding specificity and interact with the same cofactors, but perform different regulatory roles during development.

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