Lung endoderm morphogenesis: gasping for form and function

Abstract

The respiratory endoderm develops from a small cluster of cells located on the ventral anterior foregut. This population of progenitors generates the myriad epithelial lineages required for proper lung function in adults through a complex and delicately balanced series of developmental events controlled by many critical signaling and transcription factor pathways. In the past decade, understanding of this process has grown enormously, helped in part by cell lineage fate analysis and deep sequencing of the transcriptomes of various progenitors and differentiated cell types. This review explores how these new techniques, coupled with more traditional approaches, have provided a detailed picture of development of the epithelial lineages in the lung and insight into how aberrant development can lead to lung disease.

Keywords: branching morphogenesis; congenital lung disease; noncoding RNA; signaling; transcription factor.

Figure 1

Timeline of mouse and human pulmonary development, showing diseases associated with developmental defects in the pulmonary system. Mouse and human gestation periods, along with landmark events during pulmonary development, are shown. The time periods when defects in human development can lead to congenital lung disease are noted at the bottom. Abbreviations: E, embryonic day; P, postnatal day; TE, tracheoesophageal fistula.

Figure 2

Signaling interaction networks important for pulmonary endoderm development. (a)Wnt, Bmp, and Fgf signaling controls initial specification of the pulmonary endoderm, marked by expression of the transcription factor Nkx2.1. Noggin, secreted from the notochord, helps to establish a dorsal-ventral pattern of Bmp signaling to the foregut, resulting in high levels of Sox2 dorsally and Nkx2.1 ventrally. (b) During branching morphogenesis, a feedback loop between Shh and Fgf signaling promotes outgrowth and new branch formation. (c)Wnt signaling arising from either the mesoderm (Wnt2/2b) or early epithelium (Wnt7b) promotes outgrowth and differentiation of lung epithelium in part by activating Fgf signaling. Gene products are color coordinated with the lung diagram to indicate their localization to the epithelium or mesenchyme.

Figure 3

Endoderm progenitors in pulmonary development. The early lung endoderm expresses a myriad of transcriptional regulators, including Nkx2.1, Gata6, and Foxa1/2. The distal branching tip endoderm, which remains multipotent up to embryonic day (E)13.5, expresses N-myc, Sox9, Id2, and Foxp1/2. These distal tip progenitors continue to express Sox9 and Id2 after E13.5 but become restricted to the alveolar fate and generate type 1 and 2 alveolar epithelial cells (AECs), directly or indirectly through a bipotent progenitor. The proximal Sox2⁺ progenitors generate neuroendocrine (NE), secretory, and multiciliated cells.