Fig. 12. Model of GATA6 function during lung development. A model for GATA6 function in AEC-2 differentiation (i.e. SP-C expression), AEC-1 differentiation (loss of squamous epithelium and Aqp5 gene expression), and proximal airway development (reduced number of proximal airways) during lung development. Lack of SP-C expression in both the SP-C/G6en embryos and in chimeric lung tissue generated from Gata6^–/– ES cells shows that GATA6 is crucial for SP-C gene expression and thus for certain aspects of AEC-2 differentiation (Keijzer et al., 2001). Lack of AEC-1 cells and direct activation of the mouse Aqp5 proximal promoter in SP-C/G6en embryos indicate that GATA6 plays an important role in AEC-1 cell differentiation and gene expression (this report). Reduced number of proximal airway tubules indicates that disruption of distal airway differentiation in SP-C/G6en embryos leads to disrupted proximal airway development which correlates with a recent model of lung epithelial differentiation and development (Weaver et al., 1999). GATA6 may affect all of these processes through stage-specific requirements or by disrupting early lung epithelial differentiation, leading to affects observed later in development.