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

Abstract

SUMMARYEmbryonic development of the respiratory system is regulated by a series of mesenchymal-epithelial interactions that are only partially understood. Mesenchymal FGF and Wnt2/Wnt2b signaling are implicated in specification of mammalian pulmonary progenitors from the ventral foregut endoderm, but their epistatic relationship and downstream targets are largely unknown. In addition, how wnt2 and wnt2b are regulated in the developing foregut mesenchyme is unknown. We show that the Odd-skippedrelated (Osr) zinc-finger transcriptional repressors Osr1 and Osr2 are redundantly required for Xenopus lung specification in a molecular pathway linking foregut pattering by FGFs to Wnt-mediated lung specification and RA-regulated lung bud growth. FGF and RA signals are required for robust osr1 and osr2 expression in the foregut endoderm and surrounding lateral plate mesoderm (lpm) prior to respiratory specification. Depletion of both Osr1 and Osr2 (Osr1/Osr2) results in agenesis of the lungs, trachea and esophagus. The foregut lpm of Osr1/Osr2-depleted embryos fails to express wnt2, wnt2b and raldh2, and consequently Nkx2.1 + progenitors are not specified. Our data suggest that Osr1/Osr2 normally repress bmp4 expression in the lpm, and that BMP signaling negatively regulates the wnt2b domain. These results significantly advance our understanding of early lung development and may impact strategies to differentiate respiratory tissue from stem cells.

PTK7 localization and protein stability is affected by canonical Wnt ligands

“…Thus, Wnt ligands may affect PTK7 dynamics in migrating neural crest cells. For example, Wnt2b, which we have shown leads to internalization of PTK7 and colocalizes with PTK7 in intracellular vesicles, is expressed in the Xenopus branchial arches at the time of neural crest migration (Rankin et al, 2012). Neural crest cells also provide an explanation for the relevance of the inhibition of canonical Wnt signaling by PTK7.…”

Odd-skipped related-1 controls neural crest chondrogenesis during tongue development

“…Analyses of Osr1 −/− mutant mice have shown that Osr1 is required for heart and kidney development (15,16), whereas Osr2 −/− mutant mice exhibit cleft palate and supernumerary tooth formation (17,18). Osr1 and Osr2 have also been shown to regulate kidney and foregut development in Xenopus (14,19). In addition, Osr1 and Osr2 have been shown to function partially redundantly in regulating synovial joint formation during limb skeleton development in mice (20).…”

NKX2-1 Activation by SMAD2 Signaling After Definitive Endoderm Differentiation in Human Embryonic Stem Cell

“…Some but not all studies have demonstrated that high concentrations of FGF2 increase NKX2-1 expression in differentiating hESC [9,10,15]. Mou et al, found that BMP4 induces NKX2-1 expression in differentiating human induced pluripotent stem cells [16], but Rankin et al found that suppression of BMP4 signaling is required for wnt/beta-catenin-mediated lung specification in Xenopus [17]. Thus, as is true for in vivo development of pulmonary epithelium from definitive endoderm (DE), the signals/growth factors that support specification of m/hESC-derived DE to the pulmonary lineage are not yet understood.…”