R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis

Abstract

Herein, we demonstrate that Lrp6-mediated R-spondin 2 signaling through the canonical Wnt pathway is required for normal morphogenesis of the respiratory tract and limbs. We show that the footless insertional mutation creates a severe hypomorphic R-spondin 2 allele (Rspo2 Tg ). The predicted protein encoded by Rspo2Tg neither bound the cell surface nor activated the canonical Wnt signaling reporter TOPFLASH. Rspo2 activation of TOPFLASH was dependent upon the second EGF-like repeat of Lrp6. Rspo2Tg/Tg mice had severe malformations of laryngeal-tracheal cartilages, limbs and palate, and lung hypoplasia consistent with sites of Rspo2 expression. Rspo2Tg/Tg lung defects were associated with reduced branching, a reduction in TOPGAL reporter activity, and reduced expression of the downstream Wnt target Irx3. Interbreeding the Rspo2Tg and Lrp6 -alleles resulted in more severe defects consisting of marked lung hypoplasia and absence of tracheal-bronchial rings, laryngeal structures and all limb skeletal elements.

Ca v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

“…The molecular mechanism leading to CTMs is not understood and is believed to be multifactorial. CTMs have been described in mice lacking genes involved in embryonic development [e.g., sonic hedgehog (6), Wnt (83,84), bone morphogenetic protein (85,86), FGFs (87,88)]. Recently, mice with cartilage-specific deletion of Dicer 1 showed abnormal tracheal development because of a lack of ECM deposition (89).…”

Secreted and Transmembrane Wnt Inhibitors and Activators

“…In particular, abnormal limb development is manifested through a delayed maturation of the AER. Expression of Axin2 and the TopGAL transgene is significantly reduced in the AER of Rspo2 mutant mice, indicating that Rspo2 activity in the AER is mediated by Wnt/ b-catenin signaling (Nam et al 2007a;Bell et al 2008). Furthermore, double-knockout mutants of Rspo2 and LRP6 (Rspo2 Tg/Tg /LRP6 2/2 ) showed much more severe limb defects than the single-knockouts, indicating that both genes functionally interact to regulate limb development (Bell et al 2008).…”

“…Footless is a mouse mutant carrying a hypomorphic allele of Rspo2 (Rspo2 Tg/Tg ) (Bell et al 2008). Rspo2 knockout mice were generated (Nam et al 2007a;Aoki et al 2008;Bell et al 2008;Yamada et al 2009;Jin et al 2011).…”

R-spondin 2 promotes proliferation and migration via the Wnt/β-catenin pathway in human hepatocellular carcinoma

“…The R-spondin (RSPO) protein family consists of four homologous members, which are evolutionarily conserved in vertebrates and are involved in a broad range of developmental and physiological processes (5,6): RSPO1 is important for sex determination (7); RSPO2 is required for limb, laryngeal-tracheal and lung development (8); RSPO3 is critical for placental formation (9); and the mutation of RSPO4 results in inherited anonychia (10). The association between RSPO and cancer has not been extensively studied.…”