Abstract

Uterine sensitization-associated gene-1 (USAG-1) deficiency leads to enhanced bone morphogenetic protein (BMP) signaling, leading to supernumerary teeth formation. Furthermore, antibodies interfering with binding of USAG-1 to BMP, but not lipoprotein receptor-related protein 5/6 (LRP5/6), accelerate tooth development. Since USAG-1 inhibits Wnt and BMP signals, the essential factors for tooth development, via direct binding to BMP and Wnt coreceptor LRP5/6, we hypothesized that USAG-1 plays key regulatory roles in suppressing tooth development. However, the involvement of USAG-1 in various types of congenital tooth agenesis remains unknown. Here, we show that blocking USAG-1 function through USAG-1 knockout or anti-USAG-1 antibody administration relieves congenital tooth agenesis caused by various genetic abnormalities in mice. Our results demonstrate that USAG-1 controls the number of teeth by inhibiting development of potential tooth germs in wild-type or mutant mice missing teeth. Anti-USAG-1 antibody administration is, therefore, a promising approach for tooth regeneration therapy.

Highlights

  • Like beaks, nails, horns, and several eccrine glands, teeth are ectodermal organs

  • We previously reported that tooth development arrested in Runx2−/− mice, a mouse model for congenital tooth agenesis [24], was rescued in Runx2−/−/Uterine sensitization–associated gene-1 (USAG-1)−/− mice, a supernumerary mouse model [25]

  • Hair loss behind the ear and tail kink, which are the typical phenotypes associated with tabby mice, were present in all USAG-1 and EDA1 double KO mice (Fig. 1V). These results suggest that Usag-1−/− can rescue congenital tooth agenesis during early tooth development and promote morphogenesis of the whole tooth structure arrested in the late stage

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Summary

Introduction

Tooth morphogenesis is regulated by a signal transduction network involving interactions between the epithelium and mesenchyme [1,2,3]. Interactions involving positive and negative loops among bone morphogenetic protein (BMP), fibroblast growth factors, Sonic hedgehog, and Wnt pathways regulate the morphogenesis of individual teeth [1, 4]. While the number of teeth is usually strictly controlled in individual species [5], it can increase or decrease congenitally in about 1% of individuals [6,7,8]. Conditions of decreases and increases in the usual number of teeth are called tooth agenesis and supernumerary teeth, respectively. Analyses of mouse models have begun to clarify the genetic factors and molecular and pathological mechanisms underlying these conditions [4, 9]

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