Noggin Is Required for Early Development of Murine Upper Incisors

Abstract

A supplemental appendix to this article is published electronically only at http://jdr.sagepub.com/supplemental. AbstrAct BMP signaling plays crucial roles in the development of many organs, including the tooth. Equally important is BMP signaling homeostasis, as demonstrated by multiple organ defects in mice lacking the extracellular BMP antagonist Noggin. Here, we show that Noggin is initially expressed in the maxillary mesenchyme adjunct to the upper incisor at the initiation stage, and then in the developing teeth, including incisors and molars, from the bud stage. Noggin mutants develop normal molars and mandibular incisors, but form a single, medially located upper incisor that is arrested at the late bud stage. Histological and molecular marker analyses demonstrated that two distinct upper incisor placodes initiate independently at E11.5, but begin to fuse at E12.5, coupling with elevated cell proliferation rates in the developing tooth germs. We further found that Chordin and Gremlin, two other BMP antagonists, are co-expressed with Noggin in the developing lower incisor and molar teeth. These observations indicate the importance of BMP signaling homeostasis, and suggest a functional redundancy between BMP antagonists during tooth development.

The non-canonical BMP and Wnt/β-catenin signaling pathways orchestrate early tooth development

“…The in situ PLA experiments further revealed a physical interaction between Nog and Wnts in tooth germs under physiological conditions, and the elevated level of active β-catenin in Nog mutant tooth germ supports a physiological function of Nog in modulating Wnt signaling activity in vivo. Although targeted inactivation of Nog causes defects in incisors but not in molars (Hu et al, 2012), it is possible that the enhanced Wnt signaling activities in Nog −/− molars do not reach a level that could alter the molar developmental program, similar to that seen in Axin2 heterozygotes (Lohi et al, 2010). Nevertheless, our results establish a novel function for Nog as a Wnt antagonist in vivo.…”

“…4I,J). Interestingly, in Nog mutants (Nog −/− ), active β-catenin was dramatically increased in the dental epithelium, indicating that endogenous Nog, which is expressed in the dental epithelium (Hu et al, 2012), indeed modulates Wnt signaling activity in the developing tooth (Fig. 4K).…”

The Pitx2:miR-200c/141:noggin pathway regulates Bmp signaling and ameloblast differentiation

“…Cre /Dicer1 cKO mice; the overexpression of Nog has previously been shown to inhibit 3351 RESEARCH ARTICLE miR-200c regulates noggin ameloblast differentiation (Hu et al, 2012;Plikus et al, 2005); and the 3Ј-UTR of Nog was predicted to contain a conserved miR-200c binding site. Because miR-200c was one of the miRNAs shown to be differentially expressed in ameloblasts relative to the labial CL (Fig.…”

“…In addition, misexpression of the Bmp antagonist follistatin under the control of the Krt14 promoter disrupts ameloblast differentiation in the incisor, whereas a lack of follistatin leads to ectopic enamel formation on the lingual surface (Plikus et al, 2005;Wang et al, 2007;Wang et al, 2004). A lack of noggin results in fusion of the upper incisor (Hu et al, 2012). Although the function of Bmp and other signaling pathways is well documented in tooth development and renewal, little is known about the role of microRNAs (miRNAs) in these processes.…”

Bone Morphogenetic Proteins

“…Increased expression of noggin in dental epithelium causes a loss of odontogenesis in the epithelium . In contrast, in Noggin þ/2 mice, a single upper incisor is formed with normal molars and mandibular incisors (Hu et al 2012). Chordin and Gremlin, which also prevent BMP binding to the receptors, are coexpressed with noggin in the developing lower incisor and molar.…”