An FGFR1-SPRY2 Signaling Axis Limits Basal Cell Proliferation in the Steady-State Airway Epithelium

Abstract

SummaryThe steady-state airway epithelium has a low rate of stem cell turnover but can nevertheless mount a rapid proliferative response following injury. This suggests a mechanism to restrain proliferation at steady state. One such mechanism has been identified in skeletal muscle in which pro-proliferative FGFR1 signaling is antagonized by SPRY1 to maintain satellite cell quiescence. Surprisingly, we found that deletion of Fgfr1 or Spry2 in basal cells of the adult mouse trachea caused an increase in steady-state proliferation. We show that in airway basal cells, SPRY2 is post-translationally modified in response to FGFR1 signaling. This allows SPRY2 to inhibit intracellular signaling downstream of other receptor tyrosine kinases and restrain basal cell proliferation. An FGFR1-SPRY2 signaling axis has previously been characterized in cell lines in vitro. We now demonstrate an in vivo biological function of this interaction and thus identify an active signaling mechanism that maintains quiescence in the airway epithelium.

FGFR2 is required for airway basal cell self-renewal and terminal differentiation

“…GFP + basal cells from control and Fgfr2 cHet tracheae were sorted as GFP + , GSIβ4 lectin + (Balasooriya et al, 2016). Total RNA was extracted using Qiagen RNEasy Mini Kit.…”

Fgf10 Signaling in Lung Development, Homeostasis, Disease, and Repair After Injury

“…Even loss of one copy of Fgfr2 in adult mouse airway BSCs is sufficient to reduce BSC self-renewal with cells quickly becoming senescent ( Balasooriya et al, 2017 ). Interestingly, conditional deletion of Fgfr1 or Spry2 specifically in adult mouse tracheal BSCs using the Krt5 promoter causes increased ERK/AKT signaling and BSC proliferation and a block in ciliated cell differentiation ( Balasooriya et al, 2016 ), possibly due to increased Fgfr2b signaling caused by a lack of Spry2 activation by Fgfr1. This phenotype resembles that of tracheas overexpressing Fgf10 , suggesting that this Fgfr1-SPRY2 signaling axis might function to antagonize Fgf10/Fgfr2b/ERK/AKT signaling, which is required for maintaining quiescence and restricting BSC proliferation in the steady-state airway epithelium in vivo .…”

Trends in tissue repair and regeneration

“…Using clonal lineage analysis of basal and secretory cells, she showed that -under steady-state conditions -basal cells display heterogeneity and appear to undergo asymmetric cell divisions to yield two basal cells, one of which generates columnar secretory and ciliated cells in consecutive divisions. Signaling via FGFR1 that is stabilized by the inhibitor sprouty 2 is required to restrain basal cell proliferation and maintain quiescence (Balasooriya et al, 2016). In a regeneration model in the mouse airway, Purushothama Rao Tata (Duke University, Durham, USA) showed that differentiated secretory cells respond to stem cell ablation by proliferating and converting into functional basal stem cells (Tata et al, 2013).…”