Regulation of White Cell Development.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-9-SCI-9
Author(s):  
Peter E. Newburger ◽  
Sherman M. Weissman
Keyword(s):  
Transcription Factors ◽  
Base Pair ◽  
Conflicts Of Interest ◽  
Cell Development ◽  
White Cell ◽  
Hoxa Cluster ◽  
Interacting Protein ◽  
Myeloid Development ◽  
Eosinophil Granule ◽  
And Function

Abstract Abstract SCI-9 During hematopoiesis, determination of lineage and maturation to functional leukocytes depend upon cytokine-mediated changes in the transcriptional programs of progenitor and precursor cells. The classic binary branching tree of hematopoiesis now appears to be a more subtle series of gradual changes in differentiation probabilities, with competitive promotion and inhibition of lineage pathways by regulatory transcription factors such as (among others) PU.1, C/EBPα, GFI-1, EGR1/2, and NAB2 for the myeloid lineages and RUNX1, Notch-1, E2A, GATA-3, EBF, and PAX5 for lymphoid cell development. In addition, the recent discovery of regulatory non-coding RNAs (ncRNAs) has revealed another, important layer of control of hematopoiesis. The best studied members of this diverse group are the microRNAs, which often down-regulate multiple target transcripts. miRNAs involved in the regulation of myeloid development and function include miR-155, miR-223, and miR-17-19 cluster members. In addition, miR-9, miR-146a, miR-155, and miR-181a regulate the responses of immunocytes of the innate and acquired immune systems. Most recently, increasing numbers of long ncRNAs have been identified and found to regulate expression of other genes, both in cis and in trans. EGO (eosinophil granule ontogeny), a 500 base pair spliced, polyadenylated transcript regulates eosinophil granule protein gene expression. HOTAIRM1 (Hox antisense intergenic RNA, myeloid-1), a ∼500 base pair spliced polyadenylated ncRNA, affects neutrophil expression of both contiguous and distant HoxA cluster genes, as well as transcripts for CD18 integrin. Thus the control of white cell development depends not simply on a small number of key transcription factors, but rather on a complex network of interacting protein and ncRNA regulators of the transcriptional and translational programs of cell differentiation and function. Disclosures No relevant conflicts of interest to declare.

MicroRNA Regulation of Immune Cell Development and Function

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-31-SCI-31
Author(s):  
Dinesh S. Rao
Keyword(s):  
Immune Cell ◽  
Conflicts Of Interest ◽  
Myeloid Cell ◽  
Cell Development ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Nf Kappa B ◽  
Hematopoietic Development ◽  
Myeloid Development ◽  
And Function

Abstract Abstract SCI-31 The NF-kappa B pathway is a central mediator of inflammation and plays an important role in myeloid cell development. During activation of macrophages by LPS, three microRNAs (miRNAs) were initially identified as being upregulated in an NF-kappa B dependent manner. Subsequent efforts to characterize two of these miRNAs, namely miR-155 and miR-146a, have revealed important roles not only in inflammation but also in hematopoietic development. Curiously, these two miRNAs seem to play opposing roles in promoting immune cell and progenitor proliferation, and the phenotypes induced in gain and loss-of-function contexts will be discussed in detail. Specifically, miR-155 overexpression and miR-146a deficiency lead to myeloid proliferations with pathologic consequences. These differential roles are largely explained by the targets of these microRNAs, which include signal transduction regulators: SHIP1 and SOCS1 in the case of miR-155, and TRAF6 and IRAK1 in the case of miR-146a. The roles of these miRNAs as effector and feedback regulator of the NF-kappa B pathway, respectively, will be discussed in the context of myeloid development. More broadly, these studies, as well as studies of miRNAs in B-cell development, have revealed that understanding miRNA roles in these processes will illuminate new aspects of biology and pathology. For example, the regulation of hematopoietic development by these miRNAs has revealed important interconnections between pathways that previously may have been considered disparate. Moreover, these studies have begun to underscore the importance of identifying specific targets of a miRNA in a given physiologic or pathologic context. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Foxo Transcription Factors Control Regulatory T Cell Development and Function

Immunity ◽  
2011 ◽  
Vol 34 (1) ◽  
pp. 135
Author(s):  
Yann M. Kerdiles ◽  
Erica L. Stone ◽  
Daniel R. Beisner ◽  
Maureen A. McGargill ◽  
Irene L. Ch'en ◽  
...  
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Regulatory T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Foxo Transcription Factors ◽  
And Function

scholarly journals Foxo Transcription Factors Control Regulatory T Cell Development and Function

Immunity ◽  
2010 ◽  
Vol 33 (6) ◽  
pp. 890-904 ◽  
Author(s):  
Yann M. Kerdiles ◽  
Erica L. Stone ◽  
Daniel L. Beisner ◽  
Maureen A. McGargill ◽  
Irene L. Ch'en ◽  
...  
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Regulatory T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Foxo Transcription Factors ◽  
And Function

scholarly journals Complete Block of Early B Cell Differentiation in Mice Lacking the Endosomal Adaptor Protein p14

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1026-1026
Author(s):  
Marcin Lyszkiewicz ◽  
Daniel Kotlarz ◽  
Natalia Zietara ◽  
Gudrun Brandes ◽  
Jana Diestelhorst ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Adaptor Protein ◽  
Cell Development ◽  
B Cell Development ◽  
B Cell Differentiation ◽  
Knock Out ◽  
And Function

Abstract Human primary immunodeficiency caused by a point mutation in the 3' untranslated region of the endosomal adaptor protein p14 (also known as Lamtor2) resulted in severely impaired function of neutrophils, B cells, T cells and melanocytes. However, complexity of the phenotype and scarcity of human material preclude in-depth studies. Therefore, to gain insight into the role of p14 in B cell development and function, we generated loxP conditional knock-out mice. Using mb-1-Cre mice we demonstrated that loss of p14 at the preB1 stage lead to a complete block of B cell development, resulting in the absence of IgM-positive B cells. Further, to test the significance of p14 deficiency in peripheral organs, we took advantage of CD19-Cre mice, which have limited efficiency in deleting target genes in the bone marrow, but reach up to 95% efficiency in spleen. Thus, we could demonstrate that later in B cell development, p14 was essential for the generation and activation of mature B lymphocytes. While B1 cell development was maintained, splenic follicular B cells were massively reduced in the absence of p14. Furthermore, activation of B cell receptor (BCR) resulted in impaired intracellular signalling and proliferation of p14 deficient B cells. In particular, lack of p14 lead to delayed internalization of BCR and endosomal processing associated with impaired mobilization of Ca++ from intracellular stores as well as aberrant phosphorylation of BCR-associated kinases. In conclusion, our data revealed that p14 is a critical regulator of B cell development and function, which acts by modulating BCR signalling. Disclosures No relevant conflicts of interest to declare.

Ontogeny of Hematopoiesis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-4-SCI-4
Author(s):  
Elaine Dzierzak
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Transcription Factors ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Developmental Time ◽  
Hematopoietic Cell ◽  
Conditional Knockout ◽  
Hematopoietic Stem ◽  
And Function

Abstract The current challenge in hematopoietic transplantation and regeneration therapies is acquiring and/or producing a reliable and plentiful source of hematopoietic stem cells (HSCs). Given that HSCs from bone marrow, peripheral, or umbilical cord blood undergo only limited/no expansion ex vivo, there is a high interest in understanding how the adult cohort of multipotent self-renewing HSCs are generated and expanded during embryonic development. The development of HSCs in vertebrate embryos begins in the major vasculature. HSCs are generated in a short window of developmental time starting at embryonic day E10.5 until E12 in the mouse embryo, and from gestational weeks four to six in the human embryo. The first HSCs, which are as potent as bone marrow HSCs in transplantation procedures, are generated in the aorta-gonad-mesonephros (AGM) region. HSCs are found in the major vasculature – aorta, vitelline artery, and umbilical artery – subsequent to the appearance of hematopoietic cell clusters closely associated with the lumenal walls of these vessels. The relationship of HSCs to these clusters and the identification of the precursors to HSCs have been recently established through genetic, phenotypic, and real-time imaging studies. Remarkably, HSCs and hematopoietic progenitors arise directly from a subset of endothelial cells (hemogenic endothelial cells) in a natural transdifferentiation event. They are made through a process called endothelial to hematopoietic cell transition (EHT). EHT and HSC generation is in part regulated through ventral-derived developmental signals and a group of pivotal (core) transcription factors, including Runx1 and Gata2. Conditional knockout strategies show that these transcription factors are required for the generation of vascular hematopoietic clusters and HSCs, suggesting a role in hematopoietic fate induction and/or cell expansion. Interestingly, whereas both Runx1 and Gata2 are required for HSC generation, only Gata2 remains essential in HSCs after their production. We are profiling hemogenic endothelial and HSCs by RNA sequencing so as to understand the complete genetic program that leads to generation of HSCs. These results will be discussed in the context of developmental signaling pathways (BMP4, Hedgehog, etc.) that appear to impact HSC generation and expansion, and the localized dynamic expression and function of Gata2 and Runx1 in vascular endothelial and hematopoietic cluster cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Established and emergent roles for Ikaros transcription factors in lymphoid cell development and function

2020 ◽  
Author(s):  
Kaitlin A. Read ◽  
Devin M. Jones ◽  
Aharon G. Freud ◽  
Kenneth J. Oestreich
Keyword(s):  
Transcription Factors ◽  
Lymphoid Cell ◽  
Cell Development ◽  
And Function

scholarly journals Differential requirements for the Ets transcription factor Elf-1 in the development of NKT cells and NK cells

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 1880-1887 ◽  
Author(s):  
Hak-Jong Choi ◽  
Yanbiao Geng ◽  
Hoonsik Cho ◽  
Sha Li ◽  
Pramod Kumar Giri ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Nk Cells ◽  
Nk Cell ◽  
Nkt Cells ◽  
Cell Development ◽  
Intrinsic Defect ◽  
Nkt Cell ◽  
Ets Family ◽  
And Function

Abstract E26 Transformation specific (Ets) family transcription factors control the expression of a large number of genes regulating hematopoietic cell development and function. Two such transcription factors, Ets-1 and myeloid Elf-1–like factor (MEF), have been shown to play critical roles in both natural killer (NK)– and NKT-cell development, but not in the development of conventional T cells. In this study, we address the role of E74-like factor 1 (Elf-1), another Ets family transcription factor that is closely related to MEF but divergent from Ets-1, in NK- and NKT-cell development using Elf-1–deficient (Elf-1−/−) mice. Whereas the proportion of NK cells in Elf-1−/− mice was normal, the proportion of NKT cells was significantly reduced in the thymus and periphery of Elf-1−/− mice compared with wild-type (WT) mice. Although Ets-1–deficient mice lack NKT cells altogether, Elf-1−/− mice exhibited only a partial block in NKT-cell development caused by a cell-intrinsic defect in the selection, survival, and maturation of NKT cells. In addition, residual NKT cells found in Elf-1−/− mice produced less cytokine upon antigen stimulation compared with WT NKT cells. Our data demonstrate that Elf-1 plays an important and nonredundant role in the development and function of NKT cells, but is not involved in NK-cell development.

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