L'observation des nombreuses espèces au sein des métazoaires permet de rendre compte de leur formidable diversité de morphologies. Ces organismes complexes acquièrent leur plan d'organisation et leurs caractéristiques propres pendant le développement embryonnaire. Au cours de celui-ci, la morphogénèse des différentes structures anatomiques est contrôlée par des réseaux complexes de gènes intervenant dans des territoires et des moments précis. Comprendre quelles modifications des voies développementales au cours de l'évolution sont responsables de cette diversité constitue un champ important de la biologie moderne : l'évo-dévo. Pour comprendre ces modifications, il est important de pouvoir étudier ces changements sur des modèles facilement accessibles et qui possèdent une grande variabilité de formes. Les phanères des vertébrés répondent à ces critères : leur nombre, leur forme et leur taille ont été des caractères très variables au cours de la diversification des mammifères et les données déjà obtenues sur la souris permettent une expérimentation aisée. De nombreuses voies de signalisation sont impliquées dans le développement des phanères, mais une en particulier, impliquée spécifiquement dans le développement des appendices ectodermiques : la voie EDA, composée d'un ligand EDA, de son récepteur EDAR et d'un adaptateur spécifique EDARADD. Dans le but de mieux comprendre le rôle de la voie EDA au cours de l’évolution des mammifères, nous avons orienté ma thèse en 2 axes : le premier vise à étudier le rôle d’Edar dans le patterning de la dent chez la souris, et le second l’impact de la perte d’une des deux isoformes d’EDARADD au cours de l’évolution des mammifères. / The observation of the numerous metazoan species highlights their wonderful morphological diversity. These complex organisms got their body plan and their specific traits during embryonic development. During development, complex gene networks that are tightly regulated through space and time, control morphogenesis. Understanding which modifications of developmental pathways are responsible for the establishment of this diversity is one of the key questions of the biological field: Evo-Devo. To understand these modifications, it is crucial to study accessible models that are representative of this diversity. To do that, ectodermal appendages are a very good model: their number, size, and shape are highly variable during mammals diversification and data had already shown that they exhibit natural variation. Numerous signaling pathways are implicated in their development but one is very specific to them: the Eda pathway and present an big interest for the study of their evolution. To better understand the role of the Eda pathway during mammals evolution, I orientated my thesis in two part: the first one study the impact of Edar in the establishment of the mouse dental tooth row and the second the impact of gain/loss of protein isoforms of the adaptor Edaradd on the evolution of this pathway.

The general aim of this thesis was to broaden our knowledge of the signs and symptoms, genetics, and outcomes of dental implant treatment in individuals with oligodontia or ectodermal dysplasia. Article I is a population-based study in three Swedish counties of 162 individuals with oligodontia, which was a prevalence of 0.09%. The intent was to explore ways for dentists to assess symptoms from other ectodermal structures than teeth through a clinical interview and chair-side analyses. Thirty per cent had low salivary secretion rates while only 11% with no known syndrome reported symptoms from hair, nails, or sweat glands. These are, together with teeth, the ectodermal structures on which it is proposed that a clinical diagnosis of ectodermal dysplasia (ED) be based. Article II screened 93 probands with oligodontia for mutations in six genes known to cause oligodontia and hypohidrotic ED. Sequence alterations predicted to be damaging or potentially damaging were revealed in the AXIN2, MSX1, PAX9, and EDARADD genes in 14 (15%) of the probands. All mutations but one were novel. For the first time, EDARADD mutations were shown to cause isolated oligodontia. No individual who had reported ectodermal symptoms from hair, nails, or sweat glands had a mutation. Article III assessed orofacial function in individuals with different types of EDs using the Nordic Orofacial Test-Screening (NOT-S) protocol. Individuals with ED scored significantly higher in orofacial dysfunction than a healthy reference sample, especially in the Chewing and swallowing, Dryness of the mouth, and Speech domains. Article IV surveyed treatment outcome of dental implants in Swedish children up to age 16 years. In a 20-year period, only 26 patients were treated, 5 of whom had hypohidrotic ED and anodontia of the mandible. Individuals with ED had 64% failed implants compared to 6% among subjects with teeth missing due to trauma or agenesis. The main conclusions of this thesis were that (i) a check of whether one or more permanent incisors are missing will identify 65% of individuals with oligodontia and 84% of individuals missing nine teeth or more, (ii) evaluation of salivary secretion is indicated in children with oligodontia, (iii) a majority of individuals with oligodontia did not report other abnormal ectodermal organ function besides teeth, (iv) no clinical indicator discriminated between individuals with and without mutations in the tested genes, and more unidentified genes are involved in tooth morphogenesis, (v) EDARADD mutations are associated with isolated oligodontia, (vi) evaluation of orofacial function is indicated in individuals with ED, and many individuals with ED would benefit from orofacial skills training, (vii) dental implant placement is a rare treatment modality in children, (viii) individuals with hypohidrotic ED seem to present special challenges due to structural as well as direct effects of the mutations on bone, which seem to compromise osseointegration, (ix) central registers on signs and symptoms in individuals with rare disorders would help establish prevalences of various diagnoses and define treatment needs, and (x) quality registers for monitoring treatment outcomes of dental implants would promote early detection of risks and side-effects in individuals with rare disorders.

Diss. (sammanfattning) Umeå : Umeå universitet, 2010. / Härtill 4 uppsatser.