Fox transcription factors: from development to disease

Abstract

Forkhead box (Fox) transcription factors are evolutionarily conserved in organisms ranging from yeast to humans. They regulate diverse biological processes both during development and throughout adult life. Mutations in many Fox genes are associated with human disease and, as such, various animal models have been generated to study the function of these transcription factors in mechanistic detail. In many cases, the absence of even a single Fox transcription factor is lethal. In this Primer, we provide an overview of the Fox family, highlighting several key Fox transcription factor families that are important for mammalian development.

Keywords: Foregut development; Forkhead; Fox; Language acquisition; Pioneer factors; Transcription factors.

Fig. 1.

Phylogenetic tree of mouse Fox family members. The entire sequences of mouse Fox transcription factors were aligned pairwise using Geneious software. The following parameters were employed: global assignment with free end gaps, the Jukes-Cantor genetics distance model, and unweighted pair-group method with arithmetic mean. Differences with other phylogenetic trees of Fox transcription factors are likely the result of grouping by homology to the FKH DNA-binding domain only. Scale indicates the relative number of amino acid changes between proteins.

Fig. 2.

The domain structure of selected Fox family members. Shown are the domain structures of mouse FoxA1-3, FoxM1, FoxO1, FoxO3, FoxO4, FoxO6 and FoxP1-4. TAD, transactivation domain; NRD, N-terminal repressor domain; NLS, nuclear localization signal; NES, nuclear export signal; ZF, zinc finger; LZ, leucine zipper.

Fig. 3.

FoxA proteins function as pioneer factors. The schematic depicts how FoxA transcription factors are able to function as pioneer factors that control gene expression via their interaction with chromatin.

Fig. 4.

The role of FoxM1 in cell cycle regulation. FoxM1 regulates various factors involved in cell cycle regulation. No evidence for FoxM1 regulation exists for those cell cycle proteins shown in gray. Cyclin D2, but not A and E, is regulated by FoxM1. p16 is also known as Cdkn2a; SCF as Kitl; p21/p27 as Cdkn1a/Cdkn1b; and survivin as Birc5.

Fig. 5.

FoxO regulation in response to insulin signaling in mammals. The binding of growth factors to their receptors triggers a phosphorylation signaling cascade involving phosphoinositide 3-kinase (PI3K), phosphatidylinositol (4,5) bisphosphate (PIP₂), phosphatidylinositol (3,4,5)-trisphosphate (PIP₃), pyruvate dehydrogenase kinase (PDK) and Akt that ultimately results in the phosphorylation of FoxO. This phosphorylation confines FoxO to the cytoplasm. In the absence of growth factor signaling, including that of insulin, FoxO is thus present in the nucleus, where it upregulates anti-stress genes and cell cycle inhibitors. FoxO also regulates gluconeogenic genes in the mammalian liver to protect from hypoglycemia. Modified from Golson et al. (2010).