Signaling through BMP receptors promotes respiratory identity in the foregut via repression of Sox2

Abstract

SUMMARYThe mammalian foregut gives rise to the dorsally located esophagus and stomach and the ventrally located trachea and lung. Proper patterning and morphogenesis of the common foregut tube and its derived organs is essential for viability of the organism at birth. Here, we show that conditional inactivation of BMP type I receptor genes Bmpr1a and Bmpr1b (Bmpr1a;b) in the ventral endoderm leads to tracheal agenesis and ectopic primary bronchi. Molecular analyses of these mutants reveal a reduction of ventral endoderm marker NKX2-1 and an expansion of dorsal markers SOX2 and P63 into the prospective trachea and primary bronchi. Subsequent genetic experiments show that activation of canonical WNT signaling, previously shown to induce ectopic respiratory fate in otherwise wild-type mice, is incapable of promoting respiratory fate in the absence of Bmpr1a;b. Furthermore, we find that inactivation of Sox2 in Bmpr1a;b mutants does not suppress ectopic lung budding but does rescue trachea formation and NKX2-1 expression. Together, our data suggest that signaling through BMPR1A;B performs at least two roles in early respiratory development: first, it promotes tracheal formation through repression of Sox2; and second, it restricts the site of lung bud initiation.

Suppression of Bmp4 signaling by the zinc-finger repressors Osr1 and Osr2 is required for Wnt/β-catenin-mediated lung specification in Xenopus

“…If embryos were left in the BMPR inhibitor after lung specification between stages 35 and 42, we observed tracheal degeneration and hypoplastic lung buds (supplementary material Fig. S8), consistent with mouse studies demonstrating a role for BMP in maintenance of trachea fate and lung bud morphogenesis (Domyan et al, 2011;Lie et al, 2008). These data indicate that the failure of respiratory specification in Osr1/Osr2-depleted embryos is primarily due to elevated BMP signaling.…”

“…During this process in mice, Sox2 is initially expressed throughout the foregut epithelium and then around E9.5 BMP signaling suppresses Sox2 and esophagus fate in the ventral foregut. Mutual repression between Sox2 and Nkx2.1 then resolves the two lineages (Que et al, 2006;Li et al, 2008;Domyan et al, 2011). Our data suggest that BMP has a similar role in Xenopus; BMP signaling was not required for Xenopus lung specification but is necessary to maintain later tracheal fate (supplementary material Fig.…”

“…S7A). Sox2 is severely downregulated in Osr1/Osr2-MO-injected embryos (Figs 2, 3), and numerous studies have shown BMP signaling to be inhibitory to Sox2 expression (Matsushita, 2008;Domyan et al, 2011;Green et al, 2011). These data led us to hypothesize that, during normal development, Osr1/Osr2 negatively regulate bmp4 expression levels and that BMP signaling in turn restricts wnt2b and raldh2 expression to a thin strip of lpm adjacent to the presumptive pulmonary epithelium.…”

“…-/-mutants indicates that BMP signaling is dispensable for pulmonary specification, restricts the location of lung bud formation, promotes tracheal fate, and is required for proper distal differentiation and branching morphogenesis (Eblaghie et al, 2006;Li et al, 2008;Sun et al, 2008;Domyan et al, 2011;Xu et al, 2011). Despite recent progress, there are still a number of important unanswered questions about early lung development.…”

Tracheal Agenesis: Rare but Challenging

“…The etiology of this congenital anomaly is still unknown; Studies in mouse models suggested a role for the BMP type I receptor genes; however causal genes in human TA are yet to be identified [5].…”