Role of the Notch signalling pathway in tooth morphogenesis Thimios A. Mitsiadis a, * , Laure Regaudiat b , Thomas Gridley c a Department of Craniofacial Development, Facial Genetics Laboratory, GKT Dental Institute, Kings College London, Floors 27—28 Guy’s Tower, Guy’s Hospital, London SE1 9RT, UK b IMEB, Faculte´ d’Odontologie, Universite´ de la Me´diterrane´e, Marseille, France c The Jackson Laboratories, Bar Harbor, Maine, ME 04609, USA Accepted 12 October 2004 Introduction Teeth arise from progressive reciprocal inductive interactions between the stomodeal epithelium and the neural crest-derived mesenchyme. These interactions transform the tooth primordia into mineralised structures with various cell types. Sig- nalling molecules such as fibroblast growth factors (FGFs), bone morphogenetic proteins (BMPs), Wnts and sonic hedgehog (Shh) play an important role in tooth initiation, morphogenesis and cytodifferen- tiation. 1 Our previous data have suggested that the Notch signalling pathway is also involved in odonto- genesis. 2—4 The Notch signalling pathway enables adjacent cells to adopt different fates. 5—8 In Drosophila, the Notch gene encodes a transmembrane receptor with an extracellular domain carrying epidermal growth factor-like repeats and a cytoplasmic domain required for signal transduction. The Notch receptor interacts with transmembrane ligands encoded by the Delta and Serrate genes. The signal induced by ligand binding is transmitted at the intracellular part of the receptor in a process involving interac- tions with cytoplasmic and nuclear proteins. 6 Four genes encoding Notch receptors (Notch1, Notch2, Notch3, and Notch4) and five genes encod- ing ligands for the Notch receptors (Jagged1, Archives of Oral Biology (2005) 50, 137—140 www.intl.elsevierhealth.com/journals/arob KEYWORDS Jagged2; Notch signalling; Tooth; Facial development; Palatogenesis Summary Notch receptors are involved in cell fate decisions through the process of lateral inhibition or inductive signalling. Jagged2 belongs to the family of transmem- brane proteins that serve as the ligands for Notch receptors. We have analysed the expression of the Jagged2 gene in developing mouse teeth. Jagged2 expression is restricted in inner enamel epithelial cells that give rise to the ameloblasts. We have also examined the role of Jagged2 in tooth development using mutant mice that lack the domain of the Jagged2 protein required for interaction with the Notch receptors (DSL domain). Homozygous mutant mice die after birth, exhibit abnormal tooth morphology and fusions between the palatal and mandibular shelves. These results demonstrate that Notch signalling plays an essential role in tooth development. # 2004 Elsevier Ltd. All rights reserved. * Corresponding author. Tel.: +44 207 188 1799; fax: +44 207 188 1674. E-mail address: thimios.mitsiadis@kcl.ac.uk (T.A. Mitsiadis). 0003–9969/$ — see front matter # 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.archoralbio.2004.10.006