Research

Cell biological mechanisms in early development of ectodermal organ systems the tooth and salivary gland have remained elusive. We use advanced tissue imaging techniques combined with cell and molecular biology tools and transcriptomic approaches to understand development on a single cell level in living tissue and disease models. Our research is important because it answers fundamental biological questions on embryonic development. It also brings new understanding on the mechanisms of diseases caused by developmental defects, cancer cellular disease mechanisms and the results can be utilized in developing tissue regenerative treatments.

Studies in humans and in mouse models have revealed many details of genetic regulation in normal development and in hereditary diseases of ectodermal organs. The cellular mechanisms have for long remained elusive because lack of tools to study these highly dynamic processes. Our research focuses on the cellular events between the genetic signaling networks and phenotypes in transgenic mouse models. We combine conventional developmental biology with functional tissue imaging and transcriptomic studies. This allows us to directily observe how changes in cell polarity, migration and proliferation contribute to morphogenesis in whole live organisms. This knowledge is important not only for the elucidation of fundamental mechanisms of development, but also for understanding disease processes in which these mechanisms are dysregulated. Abnormal activation of developmental pathways in adults commonly leads to cancer, while dysregulated cellular responses and behavior during embryonic development result in dysplasias. A frequent finding in mouse mutants, that recapitulate the features of these disorders, is that the primary defect commonly manifests at the very earliest steps of organogenesis. Thus, a mechanistic understanding of these early developmental events is needed, if we are to explain pathogenic outcomes and design effective, preventive treatments in the future.

Building blocks of organs

Building organs requires tightly regulated interactions between different groups of cells. These interactions take place in a specific pattern and each organ has to go through specific developmental stages to from a mature functional unit. The ectodermal organs, including hair, teeth and exocrine glands have many shared features in their early development: they have similar initial shapes that are regulated by shared pathways but there is also organ specific differences. They are therefore excellent models to study mechanisms of development. By comparing different organs we can establish whether morphogenesis is carried out by minor variants of a stereotypic pathways or is it highly plastic in respect of cellular behaviors and thus a variable driving force in terms of evolution.

We are especially interested in the function of signaling centers in organ development. Signaling centers in teeth are called the initiation and enamel knots. The signaling centers are specialized small groups of cells that secrete signaling molecules and are important regulators of organogenesis regulating cell behaviors in the tissue. The main function of the signaling centers is to control cell proliferation to drive the epithelial cell rearrangement and budding. We study how the signaling centers are defined and regulated and how this translates to cellular behaviours

Understanding disease mechanisms

Failures in signaling center function at critical stages of development lead to dysplasias. Abnormal activation of developmental processes may, correspondingly, lead to neoplasias. We explore which cellular processes are the most critical determinants of dysplasias. To address these specific mechanistic questions we use fluorescent reporter mouse models crossed with mutants with ectodermal placode/budding phenotypes. The teeth and salivary gland are excellent models to study cellular behaviors with imaging methods. They can be cultured as intact tissues in a laboratory environment and are thus accessible to manipulation biological pathways and imaging. Mouse mutants with tooth invagination defects have been explored mainly for defects in the bud stage and beyond. The primary defect commonly manifests at the very earliest steps of organogenesis. Thus, a mechanistic understanding of these early developmental events is necessary.