Erythropoiesis in the adult bone marrow is primarily homeostatic, producing a constant level of erythrocytes throughout adult life. This situation is dramatically different in the fetal liver during embryogenesis and in the adult spleen following acute erythroid stress. In both of these cases, erythropoiesis rapidly produces larger numbers of erythrocytes. Given that both the fetal liver and the spleen are sites of expansive erythropoiesis it has been suggested that the molecular mechanisms that regulate erythropoiesis in the fetal liver during development and the spleen during erythroid stress are similar, but distinct from steady state adult bone marrow erythropoiesis. This connection is evident in mice mutated at the flexed-tail (f) locus. f/f mutant mice exhibit a severe fetal anemia that resolves by 2 weeks after birth. Adult f/f mice exhibit normal steady state blood parameters, however, they exhibit a severe delay in the response to acute erythroid stress. We have identified a mutation in the Smad5 gene in f/f mice. Smad5 is a signaling protein-transcription factor that acts downstream of the BMP4 receptor. BMP4 plays a key role in the development of the development of hematopoietic cells and in particular the development of the erythroid lineage. This proposal outlines experiments designed to investigate the role of the BMP4/Smad5 signaling pathway in the expansive erythropoiesis characteristic of the fetal liver during development and the spleen during the response to erythropoietic stress. We will utilize the f/f mice as a means to dissect the role of BMP4 and Smad5 in hematopoesis and erythropoiesis. First, we determine the role of BMP4 and Smad5 in the expansion and differentiation of stress erythroid progenitors in the spleen following acute stress. Second we will analyze the role of BMP4 and Smad5 in the development of hematopoietic stem cells and multipotential cells in the Aorta- Gonad-Mesonephros (AGM) region of the embryo. Third, we will analyze the role of BMP4 and Smad5 in the development and differentiation of fetal liver erythroid progenitors. These analyses will provide important basic information that could be used to develop therapies for anemia and the treatment of traumatic blood loss.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070720-04
Application #
6921312
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Qasba, Pankaj
Project Start
2002-07-01
Project End
2006-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
4
Fiscal Year
2005
Total Cost
$269,839
Indirect Cost
Name
Pennsylvania State University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Lenox, Laurie E; Shi, Lei; Hegde, Shailaja et al. (2009) Extramedullary erythropoiesis in the adult liver requires BMP-4/Smad5-dependent signaling. Exp Hematol 37:549-58
Perry, John M; Harandi, Omid F; Porayette, Prashanth et al. (2009) Maintenance of the BMP4-dependent stress erythropoiesis pathway in the murine spleen requires hedgehog signaling. Blood 113:911-8
Subramanian, Aparna; Hegde, Shailaja; Porayette, Prashanth et al. (2008) Friend virus utilizes the BMP4-dependent stress erythropoiesis pathway to induce erythroleukemia. J Virol 82:382-93
Porayette, Prashanth; Paulson, Robert F (2008) BMP4/Smad5 dependent stress erythropoiesis is required for the expansion of erythroid progenitors during fetal development. Dev Biol 317:24-35
Perry, John M; Harandi, Omid F; Paulson, Robert F (2007) BMP4, SCF, and hypoxia cooperatively regulate the expansion of murine stress erythroid progenitors. Blood 109:4494-502
Subramanian, Aparna; Hegde, Shailaja; Correll, Pamela H et al. (2006) Mutation of the Lyn tyrosine kinase delays the progression of Friend virus induced erythroleukemia without affecting susceptibility. Leuk Res 30:1141-9
Lenox, Laurie E; Perry, John M; Paulson, Robert F (2005) BMP4 and Madh5 regulate the erythroid response to acute anemia. Blood 105:2741-8
Subramanian, Aparna; Teal, Hami E; Correll, Pamela H et al. (2005) Resistance to friend virus-induced erythroleukemia in W/W(v) mice is caused by a spleen-specific defect which results in a severe reduction in target cells and a lack of Sf-Stk expression. J Virol 79:14586-94