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First published online 6 February 2008
doi: 10.1242/dev.013359

Development 135, 1049-1058 (2008)
Published by The Company of Biologists 2008
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R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis

Sheila M. Bell1, Claire M. Schreiner2, Susan E. Wert1, Michael L. Mucenski1, William J. Scott2 and Jeffrey A. Whitsett1,*

1 Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
2 Division of Developmental Biology, Cincinnati Children's Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.

* Author for correspondence (e-mail: jeff.whitsett{at}cchmc.org)

Accepted 2 January 2008

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 (Rspo2Tg). 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.

Key words: R-spondin 2, Lrp6, Lung, Larynx, Trachea, Limb, Development, Wnt signaling, Sp8, Mouse




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H. Wan, F. Luo, S. E. Wert, L. Zhang, Y. Xu, M. Ikegami, Y. Maeda, S. M. Bell, and J. A. Whitsett
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[Abstract] [Full Text] [PDF]


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