title: Ectodysplasin and Wnt pathways are required for salivary gland branching morphogenesis.
abstract: The developing submandibular salivary gland (SMG) is a well-studied model for tissue interactions and branching morphogenesis. Its development shares similar features with other ectodermal appendages such as hair and tooth. The ectodysplasin (Eda) pathway is essential for the formation and function of several ectodermal organs. Mutations in the signaling components of the Eda pathway lead to a human syndrome known as hypohidrotic ectodermal dysplasia (HED), which is characterized by missing and malformed teeth, sparse hair and reduced sweating. Individuals with HED suffer also from dry mouth because of reduced saliva flow. In order to understand the underlying mechanism, we analyzed salivary gland development in mouse models with altered Eda pathway activities. We have found that Eda regulates growth and branching of the SMG via transcription factor NF-κB in the epithelium, and that the hedgehog pathway is an important mediator of Eda/NF-κB. We also sought to determine whether a similar reciprocal interplay between the Eda and Wnt/β-catenin pathways, which are known to operate in other skin appendages, functions in developing SMG. Surprisingly and unlike in developing hair follicles and teeth, canonical Wnt signaling activity did not colocalize with Edar/NF-κB in salivary gland epithelium. Instead, we observed high mesenchymal Wnt activity and show that ablation of mesenchymal Wnt signaling either in vitro or in vivo compromised branching morphogenesis. We also provide evidence suggesting that the effects of mesenchymal Wnt/β-catenin signaling are mediated, at least in part, through regulation of Eda expression.
authors.affiliation: Developmental Biology Program, Institute of Biotechnology, University of Helsinki, P.O.B. 56, 00014 Helsinki, Finland.
authors.forename: Otso
authors.initials: O
authors.lastname: Häärä
authors.forename: Sayumi
authors.initials: S
authors.lastname: Fujimori
authors.forename: Ruth
authors.initials: R
authors.lastname: Schmidt-Ullrich
authors.forename: Christine
authors.initials: C
authors.lastname: Hartmann
authors.forename: Irma
authors.initials: I
authors.lastname: Thesleff
authors.forename: Marja L
authors.initials: ML
authors.lastname: Mikkola
mesh_terms: D000818:Animals; D053331:Ectodysplasins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D016133:Polymerase Chain Reaction; D012469:Salivary Glands / Q000196:embryology* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D053331:Ectodysplasins; D016328:NF-kappa B; D051153:Wnt Proteins