RT Journal Article
SR Electronic
T1 Lrp6-mediated canonical Wnt signaling is required for lip formation and fusion
JF Development
JO Development
FD The Company of Biologists Limited
SP 3161
OP 3171
DO 10.1242/dev.037440
VO 136
IS 18
A1 Song, Lanying
A1 Li, Yunhong
A1 Wang, Kai
A1 Wang, Ya-Zhou
A1 Molotkov, Andrei
A1 Gao, Lifang
A1 Zhao, Tianyu
A1 Yamagami, Takashi
A1 Wang, Yongping
A1 Gan, Qini
A1 Pleasure, David E.
A1 Zhou, Chengji J.
YR 2009
UL http://dev.biologists.org/content/136/18/3161.abstract
AB 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.