The role of Fgf10/Fgfr2b signaling during lung development

Abstract

Fgf10 among others is one of the most important genes of the developing lung from the beginning of organogenesis. It plays a decisive role in controlling epithelial morphogenesis (Chao et al. 2016). It is obvious to assume that Fgf10 might play an important role in both lung development and lung repair after injury. Jones and colleagues already demonstrated the effect of Fgfr2b inhibition at an early time at E 12.5 showing an arrest in epithelial branching and abnormal cellular adhesion after 9 h (Jones et al. 2018). To investigate the underlying Fgf10/Fgfr2b signaling mechanism we use a double transgenic mouse mode (Rosa26rtTA/rtTA; tet(O)sFgfr2b) which allows to attenuate the Fgfr2b activity. Lung morphometry and immunofluorescence staining were performed to identify changes in lung structure. We found that the attenuation of Fgfr2b through sFgfr2b at pseudoglandular (E14.5) and canalicular (E16.5) stages leads to less proliferation and more apoptosis. Furthermore, we could demonstrate macroscopically an arrest in epithelial branching with characteristic elongated distal branches and thicker mesenchyme. These results demonstrate that the impacts of inhibiting Fgfr2b in the pseudoglandular stage (E14.5) lead to effects on branching and proliferation. To see also the effect on the ACE II cells we used an inducible and cell specific triple transgenic mouse model (SftpcCreERT2/+;Tomatoflox/+;Fgfr2bflox/+ ). We mark the AEC II cells with RFP and block the Fgfr2b signaling in these cells. We choose the timepoints P4 and P17 to see reactions in the saccular and alveolar stages. Our results showed that the blockade of Fgfr2b signaling in AEC II progenitor cells leads at the saccular stage P4 to a decrease of Sftpc-expression in the AEC II cells. Therefore, we suggest that one of the immediate effects of Fgfr2b signaling at P4 in Sftpc-positive cells is to control the further differentiation of AEC II cells. It seems that the further development of Sftpc-positive cells depends from the presence of Fgfr2b signaling. As this study demonstrates, more detailed examinations within each stage of lung development are needed to better understand how Fgf10/Fgfr2b signaling mechanistically operates at the molecular and cellular levels to control lung organogenesis. New findings and the elaboration of processes of Fgf10/Fgfr2b signaling, which are affected on the biochemical level, may be essential to find potential targets and develop new therapeutic approaches in the future.