Update of human and mouse forkhead box (FOX) gene families

Gene expression is controlled at multiple levels, including modulation of transcriptional activity, mRNA processing, and post-translational modification of proteins. The forkhead box (FOX) gene family encodes proteins that regulate the transcription of genes participating in a number of functions -- including development of various organs, regulation of senescence or proliferation, and metabolic homeostasis. The first FOX gene to be discovered was forkhead (fkh) in Drosophila, which, when mutated, gives the insect a fork-headed appearance [1]. Independently, another group characterised FOXA1 in the rat [2]. In 1990, Weigel et al. discovered that these two proteins shared a similar DNA-binding domain, and named this domain the forkhead domain (also referred to as the winged-helix domain); this domain is well conserved among all FOX family members [3]. At about 100 amino acids in length, the prototypical forkhead domain is monomeric and consists of three alpha-helices, three beta-sheets and two large loops ('wing' regions) that flank the third beta-sheet [4]. In 1993, the crystal structure of the forkhead domain bound to DNA was solved for FOXA1 [5]. Since then, several other structures have been solved, including the DNA-binding domains of FOXK1, FOXK2, FOXM1, FOXO1, FOXO3, FOXO4, FOXP1 and FOXP2 (Protein Data Bank search[6]).Before 2000, FOX genes lacked a unified naming convention and were assigned a confusing array of names by the researchers who discovered them. The winged helix/forkhead nomenclature committee defined the FOX family as all genes/proteins having sequence homology to the canonical winged helix/forkhead DNA-binding domain; subclasses FOXA to FOXO were defined based on a phylogenetic analysis of the forkhead domain (other domains were highly divergent, and alignment was unclear between subclasses) [7]. Since then, the family has been expanded to include subclasses FOXP to FOXS.The FOX family consists of 50 members in the human genome (plus two known