The BMP4-Smad5 signaling pathway is required for the rapid expansion of erythroid progenitors in the embryo.

During development, the embryo grows at a very rapid pace, unlike seen anytime during adult life. This rapid growth place a severe demand on the embryo to deliver oxygen to the increasing tissue mass. Hence, one of the first systems to be established in the embryo is the circulatory system consisting of a network of vessels capable of carrying blood cells. This process of blood formation is predominantly erythroid initially, which lends the embryo the capacity to deliver oxygen efficiently to the growing tissues. This expansive erythropoiesis seen in the fetus is mechanistically very different from the erythropoiesis seen in the adult which is predominantly homeostatic. The only situation in the adult where there is expansive erythropoiesis as seen in the embryo is under conditions of acute anemia or rapid blood loss, which leads to a rapid expansion of erythroid progenitors in the spleen; a condition termed stress erythropoiesis. This relationship between fetal liver and adult stress erythropoiesis is evident in mice with a mutation at the flexed-tail (f) locus. f/f embryos exhibit a severe microcytic, hypochromic fetal anemia. The anemia is most severe early in fetal development and gradually improves such that the anemia resolves about two weeks after birth. As adults, f/f mice have normal blood values but are unable to respond rapidly to acute erythropoietic stress. When challenged with an acute anemia, the control mice respond by inducing the rapid expansion of erythroid progenitors in the spleen but in the f/f mice, this response is delayed. We have identified the mutation in the f/f mice to be in a gene called Smad5. Smad5 belongs to the Smad family of transcription factors and functions downstream of BMPs, specifically BMP2, 4, and 7. We have shown that the BMP4-Smad5 signaling pathway is responsible for initiating the stress erythropoietic response in the adult spleen in response to acute anemia. Work described in this thesis shows that the same BMP4-Smadd5 signaling pathway is responsible for the anemia seen in the f/f fetal livers during development. The observations described in the thesis underscore the similarities and the differences observed between fetal erythropoiesis and stress erythropoiesis seen in the adult using f/f mice as a model for studying expansive erythropoiesis.