title: Lrp6-mediated canonical Wnt signaling is required for lip formation and fusion.
abstract: 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/beta-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/beta-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/beta-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.
authors.affiliation: Department of Cell Biology and Human Anatomy, University of California, Davis, CA 95616, USA.
authors.forename: Lanying
authors.initials: L
authors.lastname: Song
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Li
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Ya-Zhou
authors.initials: YZ
authors.lastname: Wang
authors.forename: Andrei
authors.initials: A
authors.lastname: Molotkov
authors.forename: Lifang
authors.initials: L
authors.lastname: Gao
authors.forename: Tianyu
authors.initials: T
authors.lastname: Zhao
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamagami
authors.forename: Yongping
authors.initials: Y
authors.lastname: Wang
authors.forename: Qini
authors.initials: Q
authors.lastname: Gan
authors.forename: David E
authors.initials: DE
authors.lastname: Pleasure
authors.forename: Chengji J
authors.initials: CJ
authors.lastname: Zhou
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002971:Cleft Lip / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D008046:Lip / Q000033:anatomy & histology / Q000196:embryology* / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051957:MSX1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000502:physiology*; D011401:Promoter Regions, Genetic; D050697:Retinal Dehydrogenase; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D018398:Homeodomain Proteins; D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D051957:MSX1 Transcription Factor; C084119:MSX2 protein; C484084:Msx1 protein, mouse; D051153:Wnt Proteins; D000445:Aldehyde Oxidoreductases; D050697:Retinal Dehydrogenase; C508905:retinaldehyde dehydrogenase 3, mouse