Patterning and plasticity in development of the respiratory lineage

Abstract

The mammalian respiratory lineage, consisting of the trachea and lung, originates from the ventral foregut in an early embryo. Reciprocal signaling interactions between the foregut epithelium and its associated mesenchyme guide development of the respiratory endoderm, from a naive sheet of cells to multiple cell types that line a functional organ. This review synthesizes current understanding of the early events in respiratory system development, focusing on three main topics: (1) specification of the respiratory system as a distinct organ of the endoderm, (2) patterning and differentiation of the nascent respiratory epithelium along its proximal-distal axis, and (3) plasticity of the respiratory cells during the process of development. This review also highlights areas in need of further study, including determining how early endoderm cells rapidly switch their responses to the same signaling cues during development, and how the general proximal-distal pattern of the lung is converted to fine-scale organization of multiple cell types along this axis.

Figure 1. Signaling interactions during step-wise specification of the respiratory lineage

Schematic depictions of key secreted ligands and transcription factors involved in specifying the respiratory progenitors. (A) During gastrulation, signals secreted from the adjacent mesoderm and ectoderm specify the foregut endoderm, which expresses marker genes Hhex and Sox2. (B) As the gut tube folds, multiple signals interact to induce trachea and lung fate in the ventral endoderm. NOG = Noggin, CHO = Chordin

Figure 2. Signaling interactions during P-D patterning of the respiratory epithelium

Schematic depictions of key secreted ligands and transcription factors involved in patterning the developing respiratory system. (A) During lung budding, multiple ligands are secreted from epithelium and the surrounding mesenchyme to distinguish the trachea and nascent lung buds. (Modified from Que et al., 2006). (B) During lung branching morphogenesis, multiple secreted ligands and transcription factors interact to distinguish the airway epithelium versus alveolar epithelium. Left panel is a wholemount image of lung at E11.5. Boxed area is illustrated in the right panel, with the epithelium depicted in blue. Signals that promote distal fate are labeled in blue. Signals that promote proximal fate are labeled in red.

Figure 3. Differentiated cell types within the respiratory epithelium

Schematic depiction of relative locations of the various cell types in the mature lung. Notch signaling regulates the fate decision between secretory and non-secretory cell fates, while TGFβ specifically promotes the differentiation program of Clara cells. The location of putative multipotent stem cells (basal cells and BASCs) are indicated with rainbow shading. BADJ – bronchioalveolar duct junction. BASC – bronchioalveolar stem cell.