Mammalian pregnancy provides a unique window on the regulation of hematopoiesis, with massive changes in the maternal blood system at the same time that de novo hematopoietic development occurs in the fetus. A central hypothesis of this work is that these hematopoietic changes are induced in part by pregnancy-specific factors produced by the placenta. The unusual patterns of hematopoiesis may reflect novel activities, in which case analysis of placental hematopoietic hormones will reveal new regulatory pathways. Placental hormones in the cytokine superfamily in the mouse include prolactin-like proteins E (PLP-E) and F (PLP-F) which stimulate mouse megakaryocyte differentiation and synergize with other cytokines to stimulate the growth of various mouse and human myeloid precursors. PLP-E and PLP-F bind to the same receptor, which does not appear to be shared with other cytokines. PLP-E, but not PLP-F, is also expressed in the mouse bone marrow in response to low platelet levels (thrombocytopenia), and administration of this hormone leads to recovery from thrombocytopenia. The goals of this proposal are to expand our understanding of how these two hormones are expressed and how they act, and through these studies to reveal new aspects of the control of hematopoiesis and the adaptation to pregnancy.
The Specific Aims of this proposal are: (1) to identify the PLP-E and PLP-F receptor; (2) to determine how hormone binding to receptor leads to signaling events and to changes in gene expression that are distinct from the responses to other cytokines; (3) to define the effects these hormones have on hematopoiesis in vivo; and (4) to characterize how the PLP-E gene is controlled in the placenta and the bone marrow. In addition to revealing basic aspects of the control of hematopoiesis in pregnancy and in disease, these studies are expected to point to new therapeutic approaches in the treatment of thrombocytopenia and other hematopoietic disorders. ? ?
