The evolution of Fox genes and their role in development and disease

Abstract

The Fox, or forkhead box, family of transcription factors is an evolutionarily ancient gene family that has expanded to more than 40 members in the mammalian genome. Fox genes are involved in a wide range of processes; for example, from the control of the cell cycle to the differentiation of epithelia, and from placental development to the formation of the inner ear. The functional diversity in Fox proteins is achieved partially through differences in interaction partners, such as modifying enzymes and cofactors, and partially through differences in the spatio-temporal expression patterns of the Fox genes. Fox transcription factors are characterized by a common winged-helix DNA-binding motif that is related to the motif in the linker histone H1. To show the breadth of function of the Fox gene family in more detail, we focus on three Fox classes — FoxO, FoxA and FoxP — because each of these classes explains a unique and important aspect of the diverse biology of the gene family. Members of the FoxA subclass play multiple parts in organ development and metabolism, and as 'pioneer' factors in chromatin reorganization. The FoxO subclass is a central mediator of insulin signalling, controlling processes that are as diverse as longevity and glucose metabolism. The first transcription factor that was shown to function in language acquisition is FOXP2. Its homologue is important in learned vocalization in songbirds. Future research will need to focus on improving our understanding of how Fox genes select from their thousands of potential binding sites in the genome to exert their specific effects, and also on how these important genes are regulated, both at the transcriptional level as well as by post-translational modifications.