Understanding endoderm development: more than just a series of tubes.

The endoderm gives rise to a vast array of cell types, found in organs that serve vital functions including digestion, respiration, energy homeostasis, and detoxification. From an intellectual standpoint, the endoderm is still an open frontier within developmental biology, with an abundance of unanswered and fundamentally important questions. The complexity of organogenesis itself—encompassing patterning, morphogenesis, and differentiation—has attracted investigators unsatisfied with studying these processes in isolation. From a clinical standpoint, the breadth of pathologies that affect the lungs, liver, pancreas, and gut has raised interest in the development of these tissues, and in the possibility that basic insights could be exploited in future translational efforts. Molecular pathways discovered in model organisms are known to underlie human congenital birth defects (Krude et al., 2002; Wang et al., 2006; Williamson et al., 2006; Smith et al., 2010), are used to generate new tissues from pluripotent stem cells in vitro and may be involved in regeneration in vivo. Given that transplantation-based therapies can cure or ameliorate diseases of the pancreas, liver, intestine, and lung, it is a major advance for human health that scientists are now able to mimic embryonic development in vitro and create ‘‘organs in a dish.’’ Despite remarkable progress, these cells and tissues often lack the mature form and function of their adult counterparts in vivo, highlighting gaps in our mechanistic understanding of morphogenesis and maturation. For these reasons, the past decade has seen a large expansion in the number of labs that have taken on the challenge of studying this previously neglected germ layer, and the current issue of Developmental Dynamics reflects the ongoing progress of the field. Although the articles in this issue focus primarily on specific organs, the lung, pancreas, liver, and intestine, they highlight insights into fundamental processes that are shared across endoderm organogenesis. These include inductive signaling events, intrinsic regulatory networks that respond to inductive signals, lineage relationships between progenitor cells and differentiated progeny, organ size regulation, and the cellular origins of regenerating adult tissues. It is also clear that there are several areas of endoderm organ biology about which we know very little, including the molecular mechanisms underlying organ morphogenesis, the question of whether regeneration recapitulates embryonic processes, and the developmental origin of organ-specific stem cells. The diversity of endodermal organ function relies not only on the distinct gene products that characterize each organ, but also on their physical shapes: a sheet of lung endoderm stretched over the scaffold of a stomach would be of no use for either breathing or eating. Understanding the molecular mechanisms of organ morphogenesis is, therefore, a goal of both basic and translational importance. Morphogenesis is not an isolated process but both drives and responds to the behavior of progenitor cells throughout development. This is highlighted by a study in this issue, showing that the differentiation of pancreatic islet precursors is coupled to an epithelial-to-mesenchymal transition (Gouzi et al., 2011, this issue, pages 589–604). Also discussed in this issue, the development of the intestine involves complex tissue rearrangements that ultimately generate a crypt-villus architecture and an adult intestinal stem cell niche (Spence et al., 2011, this issue, pages 501–520). An important open question in this tissue is whether the stem cells responsible for its maintenance represent progenitors ‘‘left over’’ from embryogenesis, if they are generated de novo during D ev el op m en ta l D yn am ic s