Model explaining the pronounced thrombocytosis detected in Mpl transgenic mice on an Mpl knock-out background (modified after Figure 7 of Tiedt et al² ). (A top panel) A 2-kb proximal promoter (dashed line) was previously shown to drive expression of Tpo receptor (Mpl) in early megakaryocytes.⁷  Other elements (depicted as asterisks) regulating cell-type specific expression of the Mpl gene (exons in blue, introns in pink) might be located at distant sites from the proximal promoter or in the introns of the Mpl gene itself. (A botton panel) Clearance of the ligand Tpo (depicted in green) is physiologically accomplished by binding to Mpl receptor molecules (depicted as Y) on circulating platelets and on bone marrow megakaryocytes. Upon binding to Mpl, the ligand Tpo is internalized and degraded. (B top panel) The 2-kb Mpl proximal promoter (dashed line) was used to drive the expression of a transgene containing the cDNA (blue) coding for Mpl. (B bottom panel) Mpl transgenic mice on an Mpl knockout background show an increased number of bone marrow megakaryocytes and circulating platelets. While early megakaryocytes in the marrow exhibit Mpl receptor (depicted as Y) densities comparable to the wild-type mice, circulating platelets exhibit significantly lower surface Mpl densities (insert). Platelet clearance to Tpo is therefore diminished, and the higher Tpo levels are binding to the Mpl on early megakaryocytes in the marrows. This results in an expansion of this population, to the point where internalization and degradation to Tpo compensates for the decreased platelet clearance of Tpo. The expanded megakaryocyte population generates an increased number of circulating platelets. Professional illustration by Paulette Dennis.