It is known from nutritional studies that vitamin A is an important factor for normal hematopoiesis, though it has been difficult to define its precise role. The vitamin A-deficient (VAD) quail embryo provides an effective ligand "knockout" model for investigating the function of retinoids during development. The VAD embryo develops with a significant reduction in erythroid cells, which has not been noted previously. Activation of the primitive erythroid program and early expression of the erythroid marker GATA-1 occurs, though GATA-1 levels eventually decline, consistent with the erythropoietic and hemoglobin deficits. However, from its early stages, the GATA-2 gene fails to be expressed normally in VAD embryos. The bone morphogenetic protein (BMP)-signaling pathway regulates GATA-2, and BMP4 expression becomes reduced in the caudal embryonic region of VAD embryos. Adding BMP4 to cultured VAD-derived explants rescues the production of erythroid cells, whereas normal embryos cultured in the presence of the BMP antagonist noggin are defective in primitive hematopoiesis. We find that cell clusters of primitive blood islands undergo an inappropriate program of apoptosis in the VAD embryo, which can explain the deficit in differentiated primitive blood cells. We propose that vitamin A-derived retinoids are required for normal yolk sac hematopoiesis and that an embryonic retinoid-BMP-GATA-2 signaling pathway controls progenitor cell survival relevant to primitive hematopoiesis. ( IntroductionThe first hematopoietic cells develop on the extra-embryonic yolk sac in close association with the initial endothelial cells. Mesoderm-derived cell clusters or "blood islands" contain the embryonic or "primitive" erythrocytes and the surrounding endothelial structures that form the extra-embryonic vascular plexus. The association of embryonic blood and endothelial cells led to a hypothesis that both derive from a common progenitor, the hemangioblast. 1 This concept has been supported recently by overlapping gene expression programs and by in vitro lineage analysis using embryonic stem cells. 2 The developmental origin and the relationship between the hemangioblast, the hematopoietic progenitors, and the hematopoietic stem cells that ultimately seed the bone marrow for adult or "definitive" hematopoiesis are not completely defined. Meanwhile, the signaling molecules that control blood island development and primitive hematopoiesis are unknown and may be distinct from definitive hematopoietic cytokines. Primitive erythrocytes are a transient population of relatively large, hyperchromatic cells expressing embryonic globins and are not dependent on the same set of regulatory genes that are required for definitive hematopoiesis. For example, definitive but not primitive erythropoiesis is critically dependent on erythropoietin. 3 Vitamin A-derived retinoids, including retinoic acid (RA), are required for normal embryogenesis and tissue maintenance. 4 Retinoids function as signaling ligands through the activation of RAR and RXR nuclea...
The data demonstrate changes in NCX transcript and NCX protein levels as well as total RNA and proteins during human heart development. Per wet weight, NCX mRNA was 4.5 times greater at early fetal than adult stages and NCX protein was 2 times greater at adult than the early fetal stage indicating considerable post-transcriptional regulation. These findings provide new insights into the understanding of temporal changes in NCX in the developing heart at the gene level. The functional significance remains to be determined.
Members of the T cell, Ig domain and mucin domain (Tim) family of proteins have recently been implicated in the control of T cell-mediated immune responses. Tim-1 (HUGO designation HAVCR1) polymorphisms have been linked to the regulation of atopy in mice and humans, suggestive of a role in immune regulation. Tim-1 is expressed upon activation of T cells. In concert with the increased expression of Tim-1, a binding partner for the extracellular domain of Tim-1 (eTim-1) was induced on activated T cells, and mRNA expression data was consistent with the binding partner being Tim-4. We found that co-immobilized recombinant eTim-1 was able to inhibit T cell activation mediated by CD3 + CD28 mAb. eTim-1 mediated its inhibitory effects on proliferation by arresting cell cycle at G(0)/G(1) phase through regulation of cell cycle proteins. In vivo, administration of eTim-1 proteins led to a decrease in both ear (contact hypersensitivity to oxazolone) and joint (methylated BSA antigen-induced arthritis) swelling. The inhibitory activity of eTim-1 in the T(h)1-dependent models was evidence that eTim-1 is able to modulate T cell responses. Manipulation of the Tim-1 interaction with its binding partner on T cells may therefore provide a novel target for therapeutic intervention in T cell-mediated diseases.
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