The overall goal of the present work is to determine the mechanisms that permit the emergence of B lymphoid cells in the extraembryonic yolk sac and the para aortic splanchnopleura (P-Sp) and facilitate the homing of these cells into the peritoneal cavity. Though the extraembryonic yolk sac is the first site of primitive red blood cell, megakaryocyte, and macrophage production, it is controversial whether it is a site of B lymphoid emergence. An intraembryonic site, the aorta-gonad-mesonephros (AGM) region derived from the P-Sp, is currently recognized as the first site of production of HSCs capable of repopulating the hematopoietic compartment of lethally irradiated adult mice and is reported to possess the potential to give rise to B lymphoid cells upon in vitro co-culture with a certain stromal cell line. However, after the systemic circulation has commenced, it remains unclear and unproven whether the B cell progenitors are moving from the yolk sac into the P-Sp or vice versa. Indeed, the most formidable obstacle encountered when attempting to define the onset of B lymphopoiesis in the developing murine embryo, is the onset of cardiac contractions and establishment of the circulation. We have developed a novel approach that permits determination of exactly where and when hematopoietic cells emerge in the yolk sac and P-Sp. Ncx1 encodes a sodium-calcium exchange protein that is expressed only in cardiomyocytes through embryonic day (E) 11.0. Embryos lacking Ncx1 are unable to initiate cardiac contractions preventing the onset of the systemic circulation. Lack of blood flow is initially tolerated without evidence of maldevelopment, however embryos demonstrate growth retardation by E10.0 and die by E11.0. Using Ncx1 mutant and wild type (WT) mice, we have recently reported that all hematopoietic definitive progenitor cells that seed the E 10.0 fetal liver are yolk sac-derived. We have also reported that the potential for forming B lymphoid cells is present in the E 9.5 yolk sac and P-Sp of wild type and Ncx1 null mice; confirming that B lymphoid cells arise autonomously in the yolk sac and P-Sp. A host of questions now emerge that we address in the following aims:
Aim 1 : To delineate the temporal and spatial emergence of B lymphoid cells in the yolk sac and P-Sp and to define B cell specification to B1 and/or B2 lymphoid lineages from the emergent cells in these sites.
Aim 2 : To define the growth factor signaling pathways required for yolk sac and P-Sp B lymphopoiesis.
Aim 3 : Define the molecular pathway for yolk sac and P-Sp derived B cell homing to the peritoneal cavity. These studies will define the mechanism of B lymphocyte emergence, determine whether differences in B cell specification are intrinsic and restricted, and may clarify the origin of the B1 lymphocytes that secrete natural antibodies;a population of cells important in human development of autoimmune diseases and leukemia. PROJECT NARRATIVE This project aims to determine the factors required to permit the emergence of B lymphoid cells in the murine yolk sac and within the embryo and to define the molecules that are necessary for yolk sac and intraembryonic B lymphoid cells to home to the peritoneal cavity.

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This project aims to determine the factors required to permit the emergence of B lymphoid cells in the murine yolk sac and within the embryo and to define the molecules that are necessary for yolk sac and intraembryonic B lymphoid cells to home to the peritoneal cavity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hematopoiesis Study Section (HP)
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Nasseri, M Faraz
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Alphonse, Rajesh S; Vadivel, Arul; Fung, Moses et al. (2014) Existence, functional impairment, and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth. Circulation 129:2144-57
Lin, Yang; Yoder, Mervin C; Yoshimoto, Momoko (2014) Lymphoid progenitor emergence in the murine embryo and yolk sac precedes stem cell detection. Stem Cells Dev 23:1168-77
Yoshimoto, Momoko; Yoder, Mervin C; Guevara, Patricia et al. (2013) The murine Th2 locus undergoes epigenetic modification in the thymus during fetal and postnatal ontogeny. PLoS One 8:e51587
Prasain, Nutan; Meador, J Luke; Yoder, Mervin C (2012) Phenotypic and functional characterization of endothelial colony forming cells derived from human umbilical cord blood. J Vis Exp :
Yoshimoto, Momoko; Porayette, Prashanth; Glosson, Nicole L et al. (2012) Autonomous murine T-cell progenitor production in the extra-embryonic yolk sac before HSC emergence. Blood 119:5706-14
Yoder, Mervin C (2012) Human endothelial progenitor cells. Cold Spring Harb Perspect Med 2:a006692
Yoshimoto, Momoko; Montecino-Rodriguez, Encarnacion; Ferkowicz, Michael J et al. (2011) Embryonic day 9 yolk sac and intra-embryonic hemogenic endothelium independently generate a B-1 and marginal zone progenitor lacking B-2 potential. Proc Natl Acad Sci U S A 108:1468-73
Ou, Xuan; Chae, Hee-Don; Wang, Rui-Hong et al. (2011) SIRT1 deficiency compromises mouse embryonic stem cell hematopoietic differentiation, and embryonic and adult hematopoiesis in the mouse. Blood 117:440-50
Qu, Peng; Shelley, William C; Yoder, Mervin C et al. (2010) Critical roles of lysosomal acid lipase in myelopoiesis. Am J Pathol 176:2394-404
Xue, Xingkui; Pech, Nancy K; Shelley, W Christopher et al. (2010) Antibody targeting KIT as pretransplantation conditioning in immunocompetent mice. Blood 116:5419-22

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