Please activate JavaScript!
Please install Adobe Flash Player, click here for download

Cloettapreis_2004_Nr_32

non-specific proliferative signal (permissive model). To address this question in vivo, we used homologous recombination to replace the c-mpl gene with a chimeric construct encoding the extracellular domain of mpl and the cytoplasmic domain of the granulocyte colony-stimulating factor receptor (G-CSFR) (Figure 2). This chimeric receptor binds TPO, but signals through the G-CSFR intracellular domain (Stoffel et al., 1999). We found that, despite the absence of a functional mpl sig- naling domain, homozygous knock-in mice had a normal platelet count, indicating that in vivo the cytoplasmic domain of G-CSFR can function- ally replace mpl signaling to support normal megakaryopoiesis and platelet formation (Figure 2). This finding favors the permissive model, according to which cytokine receptors provide a non-specific survival or proliferation signal and argues against an instructive role of c-mpl or G-CSFR in hematopoietic cell fate decisions. Similar conclusions were reached in a knock-in model with a G-CSFR/EPOR chimera (Semerad et al., 1999). Figure 2: Summary of the conclusions reached from the analysis of homozygous mpl/G-CSFR knock-in mice. The chimeric mpl/G-CSFR binds TPO but signals through the G-CSFR cytoplasmic domain. The resulting signal does not re-program the progenitor cells to become granulocytes, instead this signal is capable of promoting megakaryopoiesis and platelet production in vivo. 43

Seiten├╝bersicht