Immunoglobulin gene rearrangement in avian B cell precursors generates surface Ig receptors of limited diversity. It has been proposed that specificities encoded by these receptors play a critical role in B lineage development by recognizing endogenous ligands within the bursa of Fabricius. To address this issue directly we have introduced a truncated surface IgM, lacking variable region domains, into developing B precursors by retroviral gene transfer in vivo. Cells expressing this truncated receptor lack endogenous surface IgM, and the low level of endogenous Ig rearrangements that have occurred within this population of cells has not been selected for having a productive reading frame. Such cells proliferate rapidly within bursal epithelial buds of normal morphology. In addition, despite reduced levels of endogenous light chain rearrangement, those light chain rearrangements that have occurred have undergone variable region diversification by gene conversion. Therefore, although surface expression of an Ig receptor is required for bursal colonization and the induction of gene conversion, the specificity encoded by the prediversified receptor is irrelevant and, consequently, there is no obligate ligand for V(D)Jencoded determinants of prediversified avian cell surface IgM receptor.The rearrangement of chicken Ig genes generates minimal antibody diversity. At the light chain (L) locus, the unique, functional V L 1 gene rearranges to the unique J L segment in all B cells (1). Similarly, at the heavy chain (H) locus, unique V H 1 and J H genes undergo rearrangement with a family of highly conserved D H elements to form a VDJ H complex of limited diversity (2, 3). Junctional diversity is limited further because of the lack of N nucleotide additions in chicken V(D)J junctions (4). A diverse repertoire of B cell specificities is generated by somatic gene-conversion events in which VD H and V L sequences in functionally rearranged VDJ H and VJ L genes are replaced by homologous sequences from upstream V L and V H pseudogenes (⌿V L and ⌿V H ) (2, 5-7).The bursa of Fabricius is the primary site of B cell lymphopoiesis in avian species, and surgical or chemical ablation of the chicken bursa profoundly disrupts the normal progression of B cell development and the generation of diversity by gene conversion (reviewed in refs. 7-10). The bursa is colonized by a single wave of B cell precursors during embryogenesis starting at about embryonic day 8 (E8) and lasting about a week (11). Within the bursa, B cell precursors first are observed in the mesenchymal tissue, and 20,000-40,000 precursors subsequently migrate across the bursal epithelial basement membrane and begin to proliferate in oligoclonal clusters or epithelial buds from which the discrete follicles of the mature bursa are derived (12, 13).Surface Ig (sIg) ϩ B cell precursors first are observed by about E9-E10, and the frequency of such cells increases rapidly during the embryonic period (14). Although Ig gene rearrangement is not intrinsically biased towar...
The bursa of Fabricius is critical to normal B-lymphocyte development in birds. During embryonic life, B-cell precursors migrate to the bursal rudiment and those which have undergone productive V(D)J recombination colonize lymphoid follicles and undergo immunoglobulin V gene diversification by gene conversion. The chicken surface IgM complex appears structurally and functionally equivalent to its mammalian counterpart, with homologs to CD79a and CD79b. Expression of a truncated Igmu chain is sufficient to drive the early stages of B-cell development in the embryo bursa. Bursal cells expressing the truncated mu receptor complex proliferate in bursal follicles, and those which contain V gene rearrangements undergo V gene diversification by gene conversion. The bursa is a gut-associated organ and antigen is focused to bursal lymphoid follicles after hatch. While expression of the truncated mu chain is sufficient to support B-cell development in the embryo, B cells expressing this receptor are rapidly eliminated after hatch. We suggest the possibility that B-cell development in the bursa after hatch is driven by encounter with antigen leading to redistribution of B cells within the lymphoid follicle, B-cell proliferation and V gene repertoire development by gene conversion.
Abstract-We identified apolipoprotein (apo)D in a search for proteins upregulated in a posttranscriptional manner similar to fibronectin in motile smooth muscle cells (SMCs). To address the function of apoD in SMCs, we cloned a partial apoD cDNA from ovine aortic (Ao) SMCs using RT-PCR. We documented a 2.5-fold increase in apoD protein but no increase in apoD mRNA in Ao SMCs 48 hours after a multiwound migration assay (PϽ0.01). Confocal microscopy revealed prominent perinuclear and trailing edge expression of apoD in migrating SMCs but not in the confluent monolayer. Stimulation of Ao SMCs with 10 ng/mL platelet-derived growth factor (PDGF)-BB increased apoD protein expression (PϽ0.05). Moreover, PDGF-BB-stimulated migration of human pulmonary artery SMCs was suppressed by knock-down of apoD using RNAi. Stable overexpression of apoD in Ao SMCs cultured in 10% fetal bovine serum promoted random migration by 62% compared with vector-transfected cells (PϽ0.01). Overexpression of apoD or addition of exogenous apoD to a rat aortic SMC line (A10) stimulated their migration in response to a subthreshold dose of PDGF-BB (PϽ0.05). This was unrelated to increased phosphorylation of ERK1/2 or of phospholipase C-␥1, but correlated with enhanced Rac1 activation. This study shows that apoD can be expressed or taken up by SMCs and can regulate their motility in response to growth factors. T he ductus arteriosus (DA) is a fetal vessel that develops a neointima in late gestation and closes on constriction after birth. Our previous studies related formation of the DA neointima to heightened vascular smooth muscle cell (SMC) migration, which is linked to increased fibronectin synthesis relative to that in SMCs from the aorta (Ao). [1][2][3][4] Subsequent studies showed that the increase in DA fibronectin synthesis is regulated by enhanced mRNA translation involving an interaction between an RNA binding protein, identified as light chain 3 (LC3) of microtubule-associated proteins 1A and 1B 3 with an AU-rich element (ARE) in the 3Ј-untranslated region (3ЈUTR) of fibronectin mRNA. An LC3 protein affinity column was then used to identify mRNAs in which enhanced translation might be similarly regulated in motile SMCs. One of the bound transcripts encoded the 3ЈUTR of apoD (unpublished data, 2004); therefore, the present study was undertaken to establish whether apoD has a role in SMC motility.ApoD is a 29-to 30-kDa glycoprotein identified in plasma. [5][6] It has a lipocalin structure predicting that it binds small hydrophobic ligands. 7 Subsequently, apoD was identified as a carrier molecule with high affinity for steroids such as progesterone, as well as arachidonic acid 8 and metabolites that enhance SMC migration. 9 ApoD, also a component of HDL, is present in human serum at concentrations of 47 to 155 g/mL. 10 It has been localized to pericytes in developing blood vessels 11 and is seen in close association with mature blood vessels in a variety of animal tissues, 12,13 most recently by our group in human atherosclerotic plaques. ...
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