In this study, we demonstrate that the absence of Sema3A was associated with significant perinatal lethality. During late embryonic development, maturation and/or differentiation defects of distal lung epithelium were observed in Sema3A mice, and the rare Sema3A mice surviving to LY2835219 postnatal day 14 or beyond exhibited profound developmental emphysema. Taken together, these data suggest that Sema3A is a critical determinant of distal lung morphogenesis. Although first identified as a mediator of axonal pathfinding during morphogenesis of the peripheral nervous system, several studies support a role for Sema3A in development and patterning of non-neuronal tissues, including salivary gland, ureter, and kidney. Prior reports demonstrated that exogenous Sema3A protein attenuated branching morphogenesis of E11.5 fetal lung explants maintained in culture, but the role of Sema3A in lung development has not been fully characterized. Using in vivo loss of function modeling, we show here that Sema3A signals modulate distal lung epithelial cell development and postnatal alveolarization. It is of interest to note that in at least two of these previously reported models, downregulation of Sema3A expression was detected using microarray analysis of lung tissue homogenate. In the first instance, significantly decreased Sema3A transcript was found after pulmonary misexpression of the epithelial specific Ets transcription factor, ELF5. ELF5 has been reported to repress distal epithelial specification and differentiation in the lung in a manner that is tightly developmentally regulated. More recently, reduced Sema3A gene expression was noted following genetic deletion of the transcriptional regulator, coactivator associated arginine methyltransferase I. The phenotype of late stage fetal lungs from CARM1 null mice was remarkably similar to what we observed in Sema3A null animals, with thickened alveolar walls, and attenuated differentiation of ATI cells. However, we previously reported that conditional deletion of Nrp-1 in the alveolar epithelium of one week old mice led to airspace enlargement in adulthood, supporting a potential role for epithelial Sema3A-Nrp-1 signaling in the processes controlling lung septation. We have not yet determined how disruption of Sema3A-induced distal epithelial cell maturation and/or differentiation might attenuate postnatal alveolar septation, although a recent report by Srisuma et al. suggested that primary abnormalities in ATII may impair epithelial-mesenchymal interactions coordinating elastogenesis and proper airspace formation. Sema3A deletion could also impair postnatal alveolarization by pathways independent of those mediating epithelial differentiation. Nrp-1 expression is not restricted to epithelium, and prior reports demonstrate that Sema3A-Nrp-1 signals regulate angioblast migration and vascular patterning, as well as differentiation of vascular precursors to endothelial cells. It has long been recognized that alveolar septation is always associated with capillary invasion.