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Final Report Summary - GPCR DESENSITIZATION (Constitutive receptor desensitization as molecular mechanism underlying cardia bifida)

Congenital heart disease is a very commonly occurring inborn malformation. Almost 1% of all newborns are affected. However, the actual number is most probably higher, as cases, where a severe heart defect would result in embryonic lethality are not included in the statistics. One of those cardiac malformations incompatible with early life is cardia bifida, which is best described by a split heart. It arises from impaired differentiation or migration of two cardiac progenitor cell clusters. Whenever these two heart fields do not fuse correctly at the midline of the early embryo, a split heart develops, which will not be connected to the vasculature properly. Thus, a cardia bifida is not capable of providing the developing embryo with proper blood circulation and with such nutrition. Although it is clear by now that both, a failure in differentiation as well as migration can produce such severe heart defect, it remains elucidated how this kind of defect is mediated on the subcellular level. Therefore, in the course of this project, we aimed to analyse the molecular mechanism for the cardia bifida in the zebrafish miles apart mutant. The mutation leading to the phenotype is within the DRY motif of a G protein-coupled receptor. Such mutation has been shown to cause constitutive receptor desensitization in heterologous cell systems. We aimed to analyse if receptor desensitization could be the underlying cause for cardia bifida in this zebrafish model.

The project was divided into two aims: In aim 1, we planned to investigate, if the receptor mutated in miles apart zebrafish would resemble a constitutively desensitized and thus non-functional receptor. Additionally, we wanted to find out, if we could change this activity state. The experiments in this part were restricted to cell culture experiments to reduce the number of animals involved. In aim 2, we wanted to transfer the results obtained in cells to zebrafish and address mechanistic questions, which could not be answered as well in cells. Zebrafish experiments as described in aim 2 were planned to overlap with the last few months of aim 1 and were the main focus of the last funding period. During the funding we could confirm our initial hypothesis towards constitutive receptor internalization as a cause for cardia bifida. Importantly, our experiments will soon be finished and we will compile our data soon in a manuscript. In addition, the gracious funding by the Marie Curie Reintegration Grant has helped me to become an independent researcher in the field of receptor signalling and heart development.

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