The FoxA factors in organogenesis and differentiation

Abstract

The genetic analysis of the Foxa genes in both total and conditional mutant mice has clearly established that organogenesis of multiple systems is controlled by this subfamily of winged helix transcription factors. These discoveries followed the establishment of the conceptional framework of the mechanism of action of the FoxA proteins as 'pioneer factors' that can engage chromatin before other transcription factors. Recent molecular and genomic studies have also shown that FoxA proteins can facilitate binding of several nuclear receptors to their respective targets in a context-dependent manner, greatly increasing the range and importance of FoxA factors in biology.

Figure 1

Pancreas development is dependent on joint action of Foxa1 and Foxa2 to activate the pancreatic master regulator Pdx1. Similarly, the two factors cooperate to guide liver, midbrain, and lung development. (A) In wild type mice, the pancreatic bud develops into a complex organ with a ductal tree, acinar tissue for synthesis of digestive enzymes, and embedded islets of Langerhans that consists of endocrine cells. In the absence of Foxa1 and Foxa2, only a rudimentary ductal system remains, resembling the phenotype of Pdx1 ablation. From Gao et al., Genes & Development 2008, with permission. (B) Foxa binding to the Pdx1 enhancers is stage dependent, with the promoter-proximal enhancer only occupied in the mature pancreatic islet. This is one example of many that Foxa sites are used conditionally.

Figure 2

Coordinate gene regulation by Foxa factors and nuclear receptors. Depending on the cell type, Foxa1 and/or Foxa2 facilitate binding of the androgen receptor (AR), estrogen receptor (ER) and glucocorticoid receptor (GR). Foxa1 also activates expression of the estrogen receptor itself.