The definitive endoderm (DE) was first defined as the innermost tissue or germ layer found in all metazoan embryos. It gives rise to a vast array of highly specialized epithelial cell types that line the respiratory and digestive systems; and contributes to associated organs such as thyroid, thymus, lungs, liver, biliary system, and pancreas. In the adult, endodermally derived organs provide many essential functions including: gas exchange, digestion, nutrient absorption, glucose homeostasis, detoxification, and blood clotting. Perturbations in endodermal organ function are the underlying cause of thousands of human diseases that afflict millions of people every year. Basic studies of endoderm organ formation have proven invaluable for understanding the genetic basis of many human congenital diseases, and continued research will probably make it possible to grow endoderm organ tissue in vitro for future transplantation-based therapies, reviewed in Spence & Wells (2007)
Toward these goals, much has been learned about endoderm organogenesis over the past 20 years. The segregation of the three primary germ layers, the endoderm, mesoderm, and ectoderm, occurs during gastrulation; and it is one of the first cell fate decisions that is made in development. Increasing evidence suggests that the endoderm and mesoderm arise from a transient common precursor cell population referred to as mesendoderm. Mesendoderm induction and commitment to the endodermal lineage are controlled by an evolutionarily conserved gene regulatory network, which consists of Nodal growth factor signaling and a core group of downstream transcription factors.
After gastrulation, a series of morphogenetic movements transforms the naïve endoderm into a primitive gut tube that is surrounded by mesoderm. During this period, the gut tube becomes regionalized along the dorsal-ventral (D-V) and anterior-posterior (A-P) axes into broad foregut, midgut, and hindgut domains that can be observed at the molecular level by restricted gene expression patterns. Endoderm patterning is controlled by a series of reciprocal interactions with nearby mesoderm tissues. As development proceeds, broad gene expression patterns within the foregut, midgut, and hindgut become progressively refined into precise domains in which specific organs will form. The foregut gives rise to the esophagus, trachea, stomach, lungs, thyroid, liver, biliary system, and pancreas; whereas the midgut forms the small intestine and the hindgut forms the large intestine (). Organ buds develop as outgrowths of endoderm epithelium that intermingle with the surrounding mesenchyme, and together these proliferate and ultimately differentiate during fetal development into functional organs. During organ formation, cell identity and the tissue morphogenesis must be tightly coordinated. These processes are controlled by many growth factor pathways including FGF, BMP, Wnt, retinoic acid (RA), Hedgehog, and Notch, which play multiple stage-specific roles during endoderm organogenesis.
Figure 1 Overview and timeline of endoderm organ formation. (a) The major events in endoderm organ formation are listed in chronological order and (b) illustrated with images of mouse embryos at e7.5 (top), e8.5, and e9.5 of development, with the endoderm shaded (more ...)
This review summarizes our current understanding of endoderm organ development in vertebrates, from the establishment of the germ layers until organ bud formation. We highlight molecular mechanisms that are evolutionarily conserved between species and the emerging principles that can be drawn from these comparative studies. Finally, we discuss how this information has enabled researchers to direct the differentiation of embryonic stem cells into tissues such as hepatocytes or pancreatic β-cells, which represent a renewable source of therapeutic tissue for transplantation-based therapies.