Foxn4 influences alveologenesis during lung development

Abstract

The terminal stage of lung development begins with the formation of the terminal sacs followed by subdivision of these sacs by septa into numerous alveoli to maximize the gas-exchange surface. This process requires coordinated action of various intrinsic and extrinsic factors as well as interaction of epithelial and mesenchymal cells. We show here that during murine lung development, the Foxn4 transcription factor is expressed in proximal airways by a subpopulation of postmitotic epithelial cells which are distinct from basal and ciliated cells and of which only a small fraction are Clara cells. Targeted inactivation of Foxn4 causes dilated alveoli, thinned alveolar walls, and reduced septa in the distal lung but no overt gross alterations in proximal airways. The alveolar defects in mutants may result from decreased platelet-derived growth factor-A (PDGFA) signaling and reduced surfactant protein B (SFTPB) expression. These data together suggest that Foxn4 may have a non-cell-autonomous role critical for alveologenesis during lung development. Developmental Dynamics 240:1512-1517,

Foxn4 promotes gene expression required for the formation of multiple motile cilia

“…Initial attempts to characterize Foxn4 function in the mouse lung using conditional mutants failed to detect a gross phenotype in the proximal airways, in that markers for various cell types, including MCCs, were not detectably changed (Li and Xiang, 2011). Our results are largely consistent with those in the mouse, in that knocking down or removing Foxn4 function in the Xenopus skin does not lead to detectable alterations in cell fate.…”

“…In addition, like Foxj1, ectopic expression of Foxn4 is sufficient to drive the formation of long ectopic cilia in cells that are not normally ciliated. We further note that in mice, Foxn4 expression, like that of Mcidas/ Gemc1 (Gmnc), appears transient in MCCs (Li and Xiang, 2011), whereas Foxj1 expression is known to persist in fully differentiated cells, presumably due to a positive-feedback loop on its own expression. Thus, Foxn4 might be crucial during a phase when multiple motile cilia are initially assembled as progenitors differentiate, while Foxj1 is not only involved in their assembly but also in their maintenance in a fully functioning cell.…”

“…Moreover, a survey of the literature indicates that Foxn4 expression is also strongly associated with MCC differentiation in the mouse: antibody staining detects transient expression of Foxn4 in progenitors during lung development (Li and Xiang, 2011) and RNA profiling consistently finds a marked increase in Foxn4 RNA expression in MCC progenitors (Hoh et al, 2012;Treutlein et al, 2014). Thus, upregulation of foxn4 by Multicilin acting through the EDM complex is likely to be a conserved event during early MCC differentiation in different organs and species.…”

“…Although Foxn4 expression occurs in MCC progenitors in the mouse lung, the analysis of conditional Foxn4 mutants failed to detect a gross MCC phenotype (Hoh et al, 2012;Li and Xiang, 2011;Treutlein et al, 2014). We nonetheless examined Foxn4 function further in Xenopus skin MCCs, using both morpholino knockdown and Cas9/CRISPR mutagenesis.…”

Foxn4: A multi-faceted transcriptional regulator of cell fates in vertebrate development

“…Because Foxn4 was thought to be specific to the nervous system [18], it was somewhat of a surprise later to observe Foxn4 expression in the mouse airway system [25]. At E14.5, Foxn4 expression turns on in a small set of cells in the epithelia of the trachea and esophagus, then spreads to the epithelia of bronchi and bronchioles by E15.5.…”