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First published online August 21, 2009
doi: 10.1242/10.1242/dev.037440

Development 136, 3161-3171 (2009)
Published by The Company of Biologists 2009
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Lrp6-mediated canonical Wnt signaling is required for lip formation and fusion

Lanying Song1,2, Yunhong Li1, Kai Wang1, Ya-Zhou Wang1,2, Andrei Molotkov2, Lifang Gao1, Tianyu Zhao1, Takashi Yamagami1, Yongping Wang1, Qini Gan1, David E. Pleasure2 and Chengji J. Zhou1,2,*

1 Department of Cell Biology and Human Anatomy, University of California, Davis, CA 95616, USA.
2 Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children-Northern California, Sacramento, CA 95817, USA.

* Author for correspondence (cjzhou{at}ucdavis.edu)

Accepted 13 July 2009

Neither the mechanisms that govern lip morphogenesis nor the cause of cleft lip are well understood. We report that genetic inactivation of Lrp6, a co-receptor of the Wnt/β-catenin signaling pathway, leads to cleft lip with cleft palate. The activity of a Wnt signaling reporter is blocked in the orofacial primordia by Lrp6 deletion in mice. The morphological dynamic that is required for normal lip formation and fusion is disrupted in these mutants. The expression of the homeobox genes Msx1 and Msx2 is dramatically reduced in the mutants, which prevents the outgrowth of orofacial primordia, especially in the fusion site. We further demonstrate that Msx1 and Msx2 (but not their potential regulator Bmp4) are the downstream targets of the Wnt/β-catenin signaling pathway during lip formation and fusion. By contrast, a `fusion-resistant' gene, Raldh3 (also known as Aldh1a3), that encodes a retinoic acid-synthesizing enzyme is ectopically expressed in the upper lip primordia of Lrp6-deficient embryos, indicating a region-specific role of the Wnt/β-catenin signaling pathway in repressing retinoic acid signaling. Thus, the Lrp6-mediated Wnt signaling pathway is required for lip development by orchestrating two distinctively different morphogenetic movements.

Key words: Msx, Wnt, Cleft lip, Lip morphogenesis, Lrp6, Retinoic acid, Mouse


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Lrp6 fuses lips

Development 2009 136: e1805. [Full Text]  





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