Role of the receptor FgfrL1 in the development of slow muscle fibers
Prof. Beat Trueb, Department of Clinical Research, University of Bern
Abstract (Lay summary see below)
Our project deals with a novel receptor called FgfrL1 and the question how this receptor controls development of slow muscle fibers. FgfrL1 is found at low levels on the surface of all cell types. It interacts with heparin and FGF ligands in a way similar to the well-known fibroblast growth factor receptors. However, it lacks the intracellular tyrosin kinase domain that would be required for transduction of the signal to the interior of the cells. At present, the molecular working mechanism of this receptor is unknown.
Mice with a targeted deletion of FgfrL1 die at birth because their diaphragm is underdeveloped and not strong enough to inflate the lungs after birth. We have demonstrated that such diaphragms specifically lack the slow muscle fibers. Thus, FgfrL1 is involved in the embryonic development of slow muscle fibers.
We plan to investigate in detail, which domains of FgfrL1 are required for activity and which domains are dispensable. For this purpose, we intend to use transgenic mouse lines since we do not have any in vitro test to measure the activity of FgfrL1. We have already produced mice that lack the intracellular domain of FgfrL1. Such mice are viable and do not show any alterations when compared to wildtype littermates. Recently, we have started to produce mice that lack parts of the extracellular region of FgfrL1, either the first Ig-domain or the second Ig-domain or the third Ig-domain. Careful analysis of such knockout mice (survival after birth, presence of slow muscle fibers in the diaphragm) should yield valuable information about a possible molecular mechanism of our receptor. Once we will know more about this mechanism, we might be able to set up an in vitro test to measure the activity of FgfrL1.
It is likely that in the long run human patients who - similar to our knockout mice - lack slow muscle fibers in their diaphragm due to muscle degeneration (muscular dystrophy) will profit from our findings.
Lay summary
Rolle des Rezeptors FGFRL1 bei der Entwicklung von langsamen Muskelfasern
Die meisten Muskeln des Menschen bestehen aus schnellen und aus langsamen Muskelfasern. Gemäss ihrem Namen können schnelle Fasern sehr schnell kontrahieren, ermüden aber auch sehr schnell. Umgekehrt kontrahieren langsame Muskelfasern viel langsamer, ermüden dafür aber viel weniger. Muskeln, die für den Dauereinsatz bestimmt sind, besitzen einen hohen Anteil an langsamen Fasern. Muskeln, die vor allem für kurzzeitige Höchstleistungen gebraucht werden, haben einen hohen Anteil an schnellen Fasern. Der Zwerchfellmuskel, der für die kontinuierliche Atmung gebraucht wird, besitzt deshalb bei Menschen wie bei Mäusen einen hohen Anteil an langsamen Muskelfasern. Bis heute ist nicht bekannt, wie die Ausbildung von schnellen und langsamen Muskelfasern während der Embryonalentwicklung gesteuert wird. Es scheint, dass Proteine wie Six1, Six4, Sox6 und Nfix den Fasertyp beeinflussen; diese Proteine werden aber vor allem im schnellen Fasertyp gefunden.
Wir haben kürzlich ein neues Protein (genannt FGFRL1) entdeckt, das unter anderem im Muskel vorkommt und das spezifisch die Entwicklung des langsamen Fasertyps zu steuern scheint. Mäuse, bei welchen das Gen für FGFRL1 defekt ist, verlieren alle ihre langsamen Muskelfasern. Solche Mäuse sterben unmittelbar nach der Geburt, weil ihr Zwerchfellmuskel zu schwach ist, um die Lungen mit Luft und Sauerstoff zu versorgen.
In unserem Forschungsprojekt wollen wir untersuchen, wie FGFRL1 die Ausbildung von langsamen Muskelfasern kontrolliert. Dazu werden wir unterschiedliche Varianten des Proteins verwenden, um zu testen, welche Anteile absolut notwendig sind und welche Anteile für die normale Funktion entbehrlich sind. Unsere Forschungsergebnisse sollten mithelfen, den Funktionsmechanismus des neuen Proteins FGFRL1 zu verstehen. Wenn dieser Mechanismus einmal bekannt ist, könnte unser Wissen verwendet werden, um Patienten mit Atemproblemen zu helfen. Solche Probleme treten vor allen bei Krankheitssyndromen wie der Muskeldystrophie auf, bei welcher der Zwerchfellmuskel langsam degeneriert.
Progetti
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