Bestimmung der Funktion von Lgd/CC2D1 in Maus
Zellbiologie
Zusammenfassung der Projektergebnisse
We have succeeded to analyse the phenotype of the Lgd double mutants in several tissues and found that the Lgds function only partly in a redundant manner. The conventional dKO results in early embryonic cessation of development around E7.5. After this stage, only empty yolk sacs were retrieved. It is still not clear whether the mutant cells die or stop proliferating. The induced conditional KO of both Lgds in the brain resulted in a failure of brain development, indicating the importance of the function of Lgd in the neuronal stem and/or precursor cells. The importance of the function of the Lgds varies, as we did not find gross defects in the epithelium of the small intestine after cdKO, besides a slight reduction in Goblet cell number. We found evidence for weak activation of the Notch pathway upon loss of Lgd function in several tissues. An important result is that the loss of function of the Lgds results in a weak activation of the Notch pathway in several issues, as has been previously discovered in the fly. The analysis of the function of Lgd1, which has so far neglected has confirmed a function during nuclear envelope sealing after mitotic division. We confirm that the phenotype of loss of Lgd1 function is only weakly penetrant, but probably occurs also in vivo. However, the weak penetrance is not based on a redundant function of Lgd2. Moreover, we find that loss of Lgd2 also causes a sealing phenotype, but with an even lower penetrance than Lgd1 loss of function. Thus, both Lgds are i9nvolved in the sealing process, but depends on the function of Lgd1. An interesting observation in this context is that the loss of Lgd function causes a mis-localisation of its interaction partner during envelope sealing, CHMP7, which organises the sealing process. We will further investigate this phenotype in the near future as it might allow the establishment of a functional assay for Lgd function in individual cells. A further important finding is that the loss of function of Lgd1 results in a significant reduction in the number of spikes of the CA neurons of the hippocampus, which is involved in learning and memory. This is important since It has been shown that Lgd1 mutant mice have deficits in learning and memory and the reduction is spikes might be the cellular cause of this defect.
Projektbezogene Publikationen (Auswahl)
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Unravelling of Hidden Secrets: The Tumour Suppressor Lethal (2) Giant Discs (Lgd)/CC2D1, Notch Signalling and Cancer. Advances in Experimental Medicine and Biology (2020, 10, 9), 31-46. Springer International Publishing.
Reiff, Tobias, Baeumers, Miriam, Tibbe, Christine, Klein, Thomas
