Protein phosphatase 1alpha is required for murine lung growth and morphogenesis

Protein phosphatase 1 (PP1) plays important roles in cell cycle control and apoptosis, two processes that impinge on morphogenesis and differentiation. Following the precedent set by other molecules regulating the cell cycle and apoptosis, we hypothesized that PP1 may have context-specific roles in development. Therefore, we have studied the spatial and temporal expression of PP1alpha during murine lung development and determined the consequences of loss of PP1alpha function on branching morphogenesis. By using an immunohistochemical approach, we show here that PP1alpha was expressed throughout the epithelium and mesenchyme upon the emergence of the lung primordium on embryonic day 10, with immunostaining exclusively extranuclear. During the late pseudoglandular stage, PP1alpha was predominantly expressed in the distal lung epithelium, whereas the mesenchyme contained very little or no PP1alpha protein. Peri- and postnatally, PP1alpha immunostaining was mostly nuclear in apparently differentiated cells, as judged by colocalization with well-known markers for lung differentiation. Exposure of fetal lung explants to antisense oligodeoxynucleotides against PP1alpha, resulted in decreased overall size of the cultured lung, a defect in forming new airways, lack of expression of surfactant protein C, and histologic signs of poor differentiation. These data suggest that PP1alpha is required for branching morphogenesis and differentiation.