The inductive role of Wnt-β-Catenin signaling in the formation of oral apparatus

Abstract

Proper patterning and growth of oral structures including teeth, tongue, and palate rely on epithelial-mesenchymal interactions involving coordinated regulation of signal transduction. Understanding molecular mechanisms underpinning oral-facial development will provide novel insights into the etiology of common congenital defects such as cleft palate. In this study, we report that ablating Wnt signaling in the oral epithelium blocks the formation of palatal rugae, which are a set of specialized ectodermal appendages serving as Shh signaling centers during development and niches for sensory cells and possibly neural crest related stem cells in adults. Lack of rugae is also associated with retarded anteroposterior extension of the hard palate and precocious mid-line fusion. These data implicate an obligatory role for canonical Wnt signaling in rugae development. Based on this complex phenotype, we propose that the sequential addition of rugae and its morphogen Shh, is intrinsically coupled to the elongation of the hard palate, and is critical for modulating the growth orientation of palatal shelves. In addition, we observe a unique cleft palate phenotype at the anterior end of the secondary palate, which is likely caused by the severely underdeveloped primary palate in these mutants. Last but not least, we also discover that both Wnt and Shh signalings are essential for tongue development. We provide genetic evidence that disruption of either signaling pathway results in severe microglossia. Altogether, we demonstrate a dynamic role for Wnt-β-Catenin signaling in the development of the oral apparatus.

Molecular and Cellular Regulatory Mechanisms of Tongue Myogenesis

“…Interestingly, the inactivation of β-catenin is associated with down-regulation of Shh expression in the tongue epithelium and reduction of Ptch1 and Gli1 expression in the underlying mesenchyme. Shh conditional inactivation right at the stage of tongue initiation results in underdevelopment of the tongue, confirming that lack of Shh signaling is sufficient to cause defective tongue formation in vivo (Lin et al, 2011).…”

Disease-associated mutations in IRF6 and RIPK4 dysregulate their signalling functions

“…Interestingly, IRF6 may be a novel effector of Wnt signalling in keratinocytes given that its transactivator function is regulated by RIPK4 [10]. The Wnt pathway has previously been shown to regulate IRF6 expression in vivo by transactivating p63 [29], and the disruption of Wnt signalling is associated with cleft lip/palate [39,40]. Wnt signalling was also recently demonstrated to directly induce keratinocyte differentiation [41].…”

Inactivation of LAR family phosphatase genesPtprsandPtprfcauses craniofacial malformations resembling Pierre-Robin sequence

“…The initial outgrowth of PA1 results from the combined activity of sonic hedgehog and canonical Wnt signaling (Yamaguchi et al, 1999;Brault et al, 2001;Jeong et al, 2004;Jin et al, 2011;Lin et al, 2011;Zhang et al, 2011;Sun et al, 2012). Importantly, conditional inactivation of β-catenin in PA1 mesenchyme leads to a severe reduction in mandibular growth, despite normal NCC migration and establishment within PA1 (Brault et al, 2001).…”