We study CNS development in two main projects: The Wnt Project and the KCC2 project.
The Wnt Project
In the Wnt project we study the effects of Wnts, and their Planar Cell Polarity downstream signalling components, on neuronal development and general cell adhesion. The Wnt family of intercellular signalling factors consists of 19 factors in vertebrates. These bind to and signal via the frizzled family of receptors (which has 10 members), often in conjunction with the Lrp5 or Lrp6 co-receptor.
Intracellular signals proceed via at least three different pathways: the canonical pathway which involves Beta-catenin stabilization, and the two non-canonical pathways. These include the Planar cell Polarity Pathway and the Calcium pathway. The biological effects of Wnts are therefore often complex and broad. During nervous system development, they act as regulators of proliferation, morphogenesis of the neural tube, and differentiation.
When we studied transgenic mouse embryos overexpressing Wnt7a in the neural tube, we found a striking effect on the cytoskeleton of the neural stem cells. This was correlated with a failure to complete closure of the neural tube during gastrulation and neurulation. Since levels of Vangl2, a component of the enigmatic Planar Cell Polarity Patwhway, were increased, we postulated that this pathway might be involved. In our present work, we study this pathway in particular.
The KCC2 Project
The KCC2 project is a joint project with Dr. Eric Herlenius group (also in the Neonatal Research Unit), and Professor Kai Kaila (University of Helsinki). KCC2 is a membrane bound Potassium-Chloride co-transporter. The onset of KCC2 expression during neuronal development correlates with the GABAA receptors switch from excitatory action during early development, to its better characterized inhibitory function. By lowering the cells chloride levels, KCC2 reverses the ion-flux through the GABAA ion channel receptor. In the KCC2 project we investigate:
- KCC2's role in the brainstem, where KCC2 is expressed but not positioned in the cell membrane during early development.
- The importance of excitatory GABAA action during development. In this project we overexpress KCC2 in transgenic mouse embryos, thereby causing a premature switch in GABAA to inhibitory action.
- Functions of KCC2 during development not related GABAA.
Luc Desferee, Postdoc
Marco Bartocci, Postdoc
Lena Bergquist, Postdoc
Maria Lindqvist, Postdoc
Zachi Horn, MD PhD
Johan Jäderstad, MD PhD
Panos Papachristou, PhD student
Matteo Bruschettini, Affiliated
Felicia Grunewald-Nordenstam, Affiliated
Professor Kai Kalia - Department of Biological and Environmental Sciences and Neuroscience Center, University of Helsinki.
Professor Ernest Arenas - Molecular Neurobiology Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet.
Dr Ola Hermanson - Department of Neuroscience, Karolinska Institutet.
Professor Eric Herlenius - Neonatal Research Unit, Department of Woman and Child Heath, Karolinska Institutet.