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

Nature Reviews Genetics volume 10, pages 233–240 (2009)Cite this article

Key Points

  • 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.

Abstract

The forkhead box (Fox) family of transcription factors, which originated in unicellular eukaryotes, has expanded over time through multiple duplication events, and sometimes through gene loss, to over 40 members in mammals. Fox genes have evolved to acquire a specialized function in many key biological processes. Mutations in Fox genes have a profound effect on human disease, causing phenotypes as varied as cancer, glaucoma and language disorders. We summarize the salient features of the evolution of the Fox gene family and highlight the diverse contribution of various Fox subfamilies to developmental processes, from organogenesis to speech acquisition.

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Figure 1: Evolutionary tree of mouse forkhead box (Fox) genes.
Figure 2: Alignment of forkhead box (Fox) genes in mice.
Figure 3: The insulin, Akt and FoxO pathway.

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Acknowledgements

The related work in the Kaestner laboratory is supported by the National Institutes of Health (NIH) grants DK-42910, DK-53839 and DK-55342, and in the Hannenhalli laboratory by NIH grant R01GM085226. The authors thank L. N. Singh for his help with preparing some of the figures. We apologize to all our colleagues whose important contributions could not be cited owing to space constraints.

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Authors and Affiliations

  1. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Sridhar Hannenhalli & Klaus H. Kaestner

  2. Penn Center for Bioinformatics, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Sridhar Hannenhalli

  3. Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Klaus H. Kaestner

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ClustalX multiple sequence alignment

ENSEMBL v50

Index of winged helix proteins

Jalview multiple alignment editor

NCBI

Pfam database

T-Coffee multiple sequence alignment package

Glossary

Positive selection

An evolutionary process by which beneficial alleles (alleles that result in increased fitness of the organism) become more frequent in a population.

Purifying selection

An evolutionary process by which deleterious alleles (alleles that result in reduced fitness of the organism) become less frequent in the population, thereby making sequences in which this process occurs more similar compared with those from different species or from individuals of the same species.

Gluconeogenic

This term describes processes that relate to gluconeogenesis, the process of synthesizing glucose from amino acids and glucose in the liver and kidney in response to fasting.

Haploinsufficiency

A condition in a diploid organism in which a single functional copy of a gene results in a phenotype such as a disease. In this case, having only 50% of gene function (50% of the protein levels present in the wild-type state) is not sufficient to fulfil the needs of the cells or the organism.

Glycogenolysis

The breakdown of glycogen that occurs during fasting. Glycogen is the storage form of carbohydrates used in animals and is broken down to liberate glucose during times of fasting.

Linker histone

The major protein component of chromatin. Linker histones allow compaction of DNA, but also play important parts in gene regulation. The linker histone H1 binds to the DNA strands as they emerge from the nucleosome particle, which is assembled by the core histones.

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Hannenhalli, S., Kaestner, K. The evolution of Fox genes and their role in development and disease. Nat Rev Genet 10, 233–240 (2009). https://doi.org/10.1038/nrg2523

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