Transcriptional networks in liver and intestinal development

Abstract

The development of the gastrointestinal tract is a complex process that integrates signaling processes with downstream transcriptional responses. Here, we discuss the regionalization of the primitive gut and formation of the intestine and liver. Anterior-posterior position in the primitive gut is important for establishing regions that will become functional organs. Coordination of signaling between the epithelium and mesenchyme and downstream transcriptional responses is required for intestinal development and homeostasis. Liver development uses a complex transcriptional network that controls the establishment of organ domains, cell differentiation, and adult function. Discussion of these transcriptional mechanisms gives us insight into how the primitive gut, composed of simple endodermal cells, develops into multiple diverse cell types that are organized into complex mature organs.

Figure 1.

Molecular mechanisms guiding digestive tract development. (A) Transcription factors are required both in specification of the endoderm as well as for expression of genes important in formation of the pancreas. Sox17 is required to activate transcriptional programs for both initial formation of the endoderm through FoxA2 and also later during pancreas specification through Pdx1. (B) Extracellular signaling differentially activates the appropriate developmental programs during organ formation. During organ specification at the 7–8-somite stage, FGF signaling from the STM promotes liver specification and suppresses the pancreas gene program in the proximal endoderm. Ventral endoderm escapes the inhibitory signal, and the pancreas gene expression is initiated. (Adapted, with permission, from Zaret 2002 © Macmillan.) (C) Interactions between endoderm (yellow) and mesoderm (black) are required for morphological changes during intestinal development. At embryonic day 8.0 (E8.0), tight association of these tissues allows for gradients of Wnt, Bmp, Fgf, and RA signaling to direct proper A-P positioning along the gut tube. (Adapted, with permission, from Spence et al. 2011 © Wiley.)

Figure 2.

Intestinal morphology changes during development. (A) At E10.5, the pseudostratified epithelium (yellow) and mesoderm (black) are tightly associated. (B) Polarized folds of epithelium form at E15 because of signaling between the prospective villus regions through BMP and Hh. (C) At E16.5, villi have been fully formed through BMP signaling. (D) Prospective crypt regions require Foxl1 and Wnt signaling from the mesoderm to maintain proper proliferative areas. (Adapted, with permission, from Spence et al. 2011 © Wiley.)

Figure 3.

Regulation of liver-specific gene expression using transcriptional networks. (A) Activation of liver-specific genes is dependent on combinations of transcription factors. HNF1α, HNF4α, and HNF6 binding is required for expression of hepatocyte-specific genes such as HNMT, PLGL, C8B, and AMBP. (B) Coexpression of transcription factors is required for maintenance of expression levels for both factors. Binding of HNF1α and HNF4α proteins to the promoters of the HNF4α and HNF1α genes, respectively, is required for robust expression of both factors.

Figure 4.

Intestinal homeostasis: Stem cells are located in the bottom of the crypt interspersed with Paneth cells. Stem cells give rise to transit-amplifying (progenitor) cells that rapidly move up the villus and differentiate into functional absorptive, goblet, and enteroendocrine cells. Once cells reach the top of the villus, they are shed into the lumen. (Reprinted, with permission, from Crosnier et al. 2006 © Macmillan.)