Differential expression of integrin α subunits supports distinct roles during lung branching morphogenesis

Abstract

Epithelial branching morphogenesis is a process by which a continuous epithelium, embedded in mesenchyme, forms tubules that extend and branch into the surrounding mesenchyme. The morphogenetic process is responsible for the architecture of many organs including the lung. Proper expression and function of extracellular matrix (ECM) molecules, such as collagens and laminins, are necessary for branching to occur normally. However, little is known about the role of epithelial cell surface molecules that mediate epithelial-matrix interactions during this process. We have studied the expression patterns of cell surface collagen and laminin integrin receptor α subunits, α1, α2, α3, and α6, in relation to that of collagen and laminin during lung branching morphogenesis. The α1 integrin subunit was present on endothelia and smooth muscles around airways and large blood vessels. The mesenchyme expressed high levels of α2 and α6 but not α3, whereas the epithelium expressed all three integrin subunits. In contrast to the widespread epithelial expression of α3 and α6, the epithelial expression of α2 was restricted to branch tips. By performing in situ hybridization and immunofluorescence on serial sections, we found that α2 protein expression on the epithelium correlated spatially and temporally with high level expression of collagen IV and laminin-1 mRNAs, suggesting that the α2-expressing epithelial cells were in the process of producing and assembling their collagen and laminin matrices. While the expression of α3 and α6 on all lung epithelia suggests that these integrins may be important to lung epithelial development, the unique expression pattern of the α2 subunit suggests that the α2β1 integrin may be important at branch tips either in the process of collagen/laminin synthesis and assembly or extension of the epithelial tubules into the mesenchyme.