| Summary: | <p>ETCHbox genes are fast-evolving homeobox genes present only in eutherian (placental) mammals which originated by duplication and divergence from a conserved homeobox gene, <em>Cone-rod homeobox</em> (<em>CRX</em>). While expression and function of <em>CRX</em> are restricted to the retina in eutherian mammals, ETCHbox gene expression is specific to preimplantation embryos. This dramatic difference could reflect the acquisition of new functions by duplicated genes or subfunctionalization of pleiotropic roles between <em>CRX</em> and ETCHbox genes. To resolve between these hypotheses, we compared expression, sequence and inferred function between <em>CRX</em> of metatherian (marsupial) mammals and ETCHbox genes of eutherians. We find the metatherian <em>CRX</em> homeobox gene is expressed in early embryos and in eyes, unlike eutherian <em>CRX</em>, and distinct amino acid substitutions were fixed in the metatherian and eutherian evolutionary lineages consistent with altered transcription factor specificity. We find that metatherian <em>CRX</em> is capable of regulating embryonically expressed genes in cultured cells in a comparable way to eutherian ETCHbox. The data are consistent with <em>CRX</em> having a dual role in eyes and embryos of metatherians, providing an early embryonic function comparable to that of eutherian ETCHbox genes; we propose that subfunctionalization of pleiotropic functions occurred after gene duplication along the placental lineage, followed by functional elaboration.</p>
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