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The image above shows a coronal tissue section of a mouse brain including the cerebellum (upper part), scanned on a sub-cellular scale using automated fluorescence microscopy. The markers DAPI (blue), EGFP (green) and 8-oxo-dG (red) stain the cell nuclei, parvalbumin-expressing protein and the soma of cells displaying oxidative stress respectively.
Together with the ubiquitous calmodulin, the EF-hand containing calcium-binding proteins (CaBPs) parvalbumin (PV), calbindin-D28k (CB) and calretinin (CR) are the most abundantly expressed members of this family in the brain. Formerly, they were classified as simple buffers serving to “clamp” the intracellular calcium concentration [Ca2+]i. But recent studies regularly using transgenic mice have revealed these molecules to play pivotal roles in Ca2+ homeostasis and signaling. The three proteins are important for synaptic plasticity and related rhythmic activities within neuronal networks. The lack of any of these proteins in knockout mice induces specific compensation mechanisms including changes in cell morphology and organelle biosynthesis. Furthermore, CR is a specific marker for mesotheliomas, a tumor derived from the lining of the body cavity (peritoneum), and CR expression is also observed in a majority of poorly differentiated colon tumors.
We are interested in the specific functions of the three proteins PV, CR and CB in all the organs where they are expressed. All three are found in subpopulations of nerve cells, PV also in fast-twitch muscles. In the distal nephron of the kidney CB and PV are implicated in the fine-tuning of Ca2+ resorption.
As research models, we use transgenic mice deficient for these three CaBPs and mice ectopically expressing PV in the brain. These animals are used to detect changes at the level of I) morphology (e.g. light (confocal)- and electron microscopy), II) molecules implicated in Ca2+ homeostasis (RT-qPCR, Western blots, ELISA, immunohistochemistry) and III) organ function (muscle, kidney, brain). We also perform tests to define the behavioral phenotype of mice deficient for either one or combinations of these CaBPs. For instance, mice deficient for PV (or with reduced PV levels in heterozygous (PV+/-) mice) show all the core symptoms of autism spectrum disorder (ASD) including impaired social interaction and repetitive, ritualistic behavior. For the projects related to tumor biology we work with cell culture models of mesotheliomas and colon cancer.
How do buffers with different affinities and kinetic properties affect short-term modulation of synaptic plasticity? What are the functional consequences at the level of neuronal networks (e.g. oscillations)? How do these changes at the network level affect the behavior of transgenic mice? How are PV expression levels linked to the core symptoms seen in autism spectrum disorder (ASD) patients and ASD mouse models?
How are other components of the calcium homeostasome affected by the absence of Ca2+ buffers? What are the mechanisms that lead to these homeostatic compensations/ adaptations? Could these secondary alterations be the cause for certain neurological phenotypes (e.g. epilepsy, schizophrenia, depression)?
Are specific Ca2+ buffers, in particular CR, only helpful markers for tumor identification or might they be involved in tumorigenesis? May these Ca2+ buffers have additional roles as Ca2+ sensor molecules? How is their expression regulated in normal vs. tumor cells? May the Ca2+ buffer and sensor CR be a putative target for cancer treatment?