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dose-dependent fashion (Stoffel et al., 1996). Thus, serum TPO protein is being regulated directly through adsorption by platelets (Figure 1). Consistent with this model, platelets deficient for c-mpl were unable to bind and absorb TPO (de Sauvage et al., 1996; Gurney et al., 1994). Figure 1: Autoregulation of TPO serum levels. The liver produces constant amounts of TPO, which is transported to the bone marrow through the blood vessels. TPO leads to an increase of platelet production and results in a higher platelet count. Platelets express the TPO- receptor. They are able to bind and degrade circulating TPO protein and thereby exert a negative feedback. One very interesting question is how specificity of the in vivo effects of TPO, i.e. the selective increase of platelets in the peripheral blood, can be explained. Since c-mpl is expressed on early hematopoietic progeni- tors and stem cells, one possibility is that signals generated by TPO and its receptor act by instructing the progenitors to commit to a specific hematopoietic lineage (instructive model). Alternatively, lineage specif- icity could be also achieved by restricting the expression of the recep- tor to cells of the appropriate lineage. According to this theory, the signals generated by the ligand-receptor interaction primarily permit the survival and proliferation of pre-determined progenitors through a 42