ReviewThe evolution of homeobox genes: Implications for the study of brain development
Introduction
Genes belonging to the homeobox superfamily are characterised by possession of a recognisable 180-nucleotide sequence (the homeobox) encoding a 60-amino acid motif known as the homeodomain. Many homeobox genes act as transcription factors regulating gene expression during developmental patterning or cell differentiation. Indeed, mutations in homeobox genes can cause dramatic changes to developmental programs in a wide range of organisms, including humans [1]. Considering the complexity of neural development in vertebrates, it is not surprising that homeobox genes have roles in the embryonic brain. Examples include the Otx and Emx family genes (Otx1, Otx2, Emx1, Emx2) implicated in forebrain and midbrain development, Dmbx1 in midbrain and hindbrain, Gbx, En and Pax-2/5/8 family genes in formation of the midbrain–hindbrain organiser region, and many Hox genes in hindbrain patterning.
Making sense of the bewildering diversity of homeobox genes, within the context of a dynamically changing and complex developing system, is a major challenge. We propose that taking an evolutionary approach can help make sense of diversity. Here we describe the diversity of homeobox genes, and demonstrate how molecular phylogenetic analyses combined with chromosomal mapping have provided a detailed insight into the evolutionary history of one group of homeobox genes: the ANTP class.
Section snippets
The diversity of homeobox genes
Secondary structure predictions, plus crystal structures, indicate that the homeodomain encodes three principal alpha helices; the more C-terminal two of which form a helix-turn-helix fold, while the more N-terminal helix lies across this fold, stabilising it [19]. The homeodomain motif confers DNA-binding properties to the protein, and many homeodomain proteins are known to be transcription factors regulating the activity of other genes. Homeobox genes must have originated early in eukaryotic
The diversity of ANTP class genes
The ANTP and PRD classes can be split, in turn, into subdivisions (Fig. 1). Most notably, molecular phylogenetics divides the ANTP class into the NK-like genes and the Hox/ParaHox-related group. These two groups can each be subdivided into a series of gene families, containing very closely related genes. For example, the Hox/ParaHox-related group in humans includes the Hox, Cdx, Gsx, Xlox, Evx, Mox, En, Gbx and Mnx gene families. Each gene family contains from one to several genes. Thus, the
Homeobox gene duplication in vertebrates
Most of the above inferences concerning the evolutionary history of homeobox genes have come from molecular phylogenetic analyses, based on homeodomain sequence similarities. Chromosomal position provides additional and complementary information. Tandem gene duplication is expected to result in physical linkage of genes, at least temporarily. In some cases, such as the well-known Hox genes, the physical linkage can remain very tight, due to functional constraints. In many other cases, there may
The origins of homeobox gene families
Can we use data on chromosomal position to make inferences about earlier events in homeobox gene evolution? In particular, can we determine how an original ANTP gave rise to the large number of distinct gene families in the earliest bilaterians animals (long before the origin of vertebrates)? Unfortunately, there is a problem with using data from the human genome to make inferences of this kind. The problem resides in the large-scale, or genome, duplications that occurred early in vertebrate
Implications for brain development and evolution
Knowledge of the evolutionary history of homeobox genes is important for several reasons, not least because it imposes a logical structure onto an otherwise mind-numbing list of genes. More importantly, we suggest that taking account of the evolutionary approach has important implications for understanding the roles of homeobox genes in brain development and evolution.
The first way in which an evolutionary approach is vital is as a basis for gene nomenclature. Only when we understand how genes
Acknowledgements
We thank Filipe Castro for suggesting the layout of Fig. 1. and David Ferrier for the AmphiMnx and AmphiEvxA photographs in Fig. 2. This research was funded by the Human Frontiers Science Program.
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