Role of GATA factors in development, differentiation, and homeostasis of the small intestinal epithelium

Abstract

The small intestinal epithelium develops from embryonic endoderm into a highly specialized layer of cells perfectly suited for the digestion and absorption of nutrients. The development, differentiation, and regeneration of the small intestinal epithelium require complex gene regulatory networks involving multiple context-specific transcription factors. The evolutionarily conserved GATA family of transcription factors, well known for its role in hematopoiesis, is essential for the development of endoderm during embryogenesis and the renewal of the differentiated epithelium in the mature gut. We review the role of GATA factors in the evolution and development of endoderm and summarize our current understanding of the function of GATA factors in the mature small intestine. We offer perspective on the application of epigenetics approaches to define the mechanisms underlying context-specific GATA gene regulation during intestinal development.

Keywords: GATA; endoderm; intestinal development; intestinal differentiation; intestinal epithelium.

Fig. 1.

Vertebrate GATA factors contain highly conserved zinc fingers. A: general structure of vertebrate GATA factors. Vertebrate GATA factors contain activation domains (AD) at the NH₂ terminus (yellow), 2 highly conserved zinc fingers (pink) with adjacent basic regions (BR, light blue), a nuclear localization signal (NLS), and a COOH-terminal domain (CTD). B: general structure of GATA zinc fingers. GATA zinc fingers consist of 4 cysteine residues (type IV), Cys-X₂-Cys-X₁₇-Cys-X₂-Cys, that coordinate a divalent zinc ion.

Fig. 2.

Evolution of GATA factors in Metazoa coincides with evolution of endoderm. Although GATA factors have not been identified in choanoflagellates or members of the phylum Poriferae, a single, ancient GATA factor was characterized in cnidarian diploblasts (orange). Evolution of GATA1/2/3 (red) and GATA4/5/6 (yellow) orthologs coincided with evolution of mesoderm and bilateral symmetry in triploblastic protostomes. Noteworthy was a biased expansion of GATA4/5/6 orthologs. A single member of each GATA subfamily is present in early triploblastic deuterostomes, which eventually expanded to 3 members in each subfamily in vertebrates.

Fig. 3.

Multiple GATA factors act sequentially in endoderm and gut development in protostome invertebrates. A and B: GATA regulatory pathways in gut development for Caenorhabditis elegans and Drosophila melanogaster. For consistency, A and B, were generated from the foundation established in Kormish et al. (reviewed in Ref. 55) and Murakami et al. (reviewed in Ref. 87), respectively. Endoderm and its progenitors and terminal gut derivatives are shown in pale yellow. GATA1/2/3 orthologs are indicated in red, GATA4/5/6 orthologs in yellow, and non-GATA factors in blue. Interactions are described in detail in the text.

Fig. 4.

Gata4/5/6 regulate endoderm development in Xenopus and zebrafish. A and B: placement of Gata factors in the progressive commitment of mesendoderm to endoderm for Xenopus laevis and Danio rerio (zebrafish). For consistency, A and B were generated from the basis established by Shivdasani (reviewed in Ref. 102). Gata4/5/6 orthologs are depicted in yellow and non-Gata factors in blue. Interactions are described in detail in the text.

Fig. 5.

GATA6 specifies primitive endoderm in the early mouse blastocyst. A: distribution of primitive endoderm (PrE) and epiblast (Epi) progenitors in early and late mouse blastocyst. PrE (yellow) and Epi (light blue) progenitors are randomly distributed in the inner cell mass (ICM) at embryonic day 3.5 (E3.5). Trophoectoderm (TE, pink) cells make up the peripheral cell layer. By E4.5, PrE cells are localized to the surface of the blastocoel cavity; Epi cells are restricted to the inner region of the ICM. B: model for FGF signaling in PrE formation. Fgf4 expression is upregulated in Epi progenitor cells; FGF receptor 2 (Fgfr2) expression is increased in PrE progenitors. FGF4 secreted by Epi progenitors is thought to interact with FGFR2, which, in turn, activates GRB2 and MAPK in PrE progenitors, resulting in induction of Gata6 expression and simultaneous repression of Nanog expression, promoting PrE fate while inhibiting Epi fate. For consistency, A and B were generated from the foundation published by Takaoka and Hamada (reviewed in Ref. 109).

Fig. 6.

Regional function and lineage differentiation of mouse small intestinal epithelium are tightly controlled by multiple regulatory proteins. A: specific functions of the small intestine are regionally segregated. The main function of the jejunum (blue) is general absorption of fat, protein, and carbohydrate. Although these functions are conducted throughout the small intestine, the duodenum (green) is specifically tasked with iron absorption, while the ileum (purple) is responsible for bile acid and vitamin B₁₂ absorption. B: crypt-villus structure enables the small intestinal epithelium to regenerate itself with a precise distribution of highly diverse cell lineages. Stem cells in crypts, including rapidly cycling crypt base columnar cell (CBC) and quiescent cells located at the +4 position, produce proliferating transit-amplifying (TA) cells that differentiate as they migrate out of the crypt and onto villi or, in the case of Paneth cells, as they migrate to the base of crypts. C: stem/progenitor cells in crypts undergo a series of decisions as they terminally differentiate. Regulatory proteins are shown next to cells in which they are expressed and/or have a role in the differentiation process. HES1, hairy and enhancer of split 1; ATOH1, atonal homolog 1; DLL1, delta-like 1; GF1, growth factor-independent 1; SPDEF, sam pointed domain-containing Ets transcription factor; SOX9, SRY box-containing gene 9; EPHB3, ephrin type B receptor 3; NEUROG3, neurogenin 3; BMP, bone morphogenetic protein. The function of these regulatory proteins is described in detail in the text.

Fig. 7.

Gata4 expression coincides with transitions in absorptive enterocyte gene expression in the distal ileum. Proximal-distal expression patterns of 3 distinct gene sets are shown. “Intestinal” gene set, expressed throughout the small intestine (black), is exemplified by sucrase isomaltase (Si) and fatty acid-binding protein 2 (Fabp2); “jejunal” gene set (blue) is exemplified by lactase (Lct) and fatty acid-binding protein 1 (Fabp1); “ileal” gene set (purple) is exemplified by solute carrier family 10, member 2 (Slc10a2) and fatty acid-binding protein 6 (Fabp6).

Fig. 8.

GATA4 and GATA6 regulate multiple processes in the mature mouse intestine. Two pathways have been identified: one is mediated by GATA4 (GATA4-specific pathway) and the other by GATA4 or GATA6 (GATA4/GATA6-redundant pathway). In the GATA4-specific pathway, GATA4 activates the jejunal gene set, likely in cooperation with hepatocyte nuclear factor-1α (HNF1α), while repressing the ileal gene set, possibly in cooperation with friend of GATA type 1 (FOG1). In the GATA4/GATA6-redundant pathway, GATA4 and GATA6 are redundant for 4 main small intestinal functions: 1) absorptive enterocyte gene expression by activating lipid-binding proteins and apolipoproteins (“lipid gene set”) and repressing specific colonic genes (“colonic gene set”), 2) crypt cell proliferation, likely in cooperation with CDX2, 3) enteroendocrine cell commitment by promoting Neurog3 expression, and 4) Paneth cell differentiation by promoting a terminal Paneth program while inhibiting a goblet program in committed (SOX9-, EPHB3-positive) Paneth progenitors. GATA factors are indicated in yellow and non-GATA factors in blue.