Journal articles: 'Lineage decision'

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Karasek, Challis, Mohamed Ashry, Chad S. Driscoll, and Jason G. Knott. "A tale of two cell-fates: role of the Hippo signaling pathway and transcription factors in early lineage formation in mouse preimplantation embryos." Molecular Human Reproduction 26, no. 9 (July 9, 2020): 653–64. http://dx.doi.org/10.1093/molehr/gaaa052.

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Abstract In mammals, the first cell-fate decision occurs during preimplantation embryo development when the inner cell mass (ICM) and trophectoderm (TE) lineages are established. The ICM develops into the embryo proper, while the TE lineage forms the placenta. The underlying molecular mechanisms that govern lineage formation involve cell-to-cell interactions, cell polarization, cell signaling and transcriptional regulation. In this review, we will discuss the current understanding regarding the cellular and molecular events that regulate lineage formation in mouse preimplantation embryos with an emphasis on cell polarity and the Hippo signaling pathway. Moreover, we will provide an overview on some of the molecular tools that are used to manipulate the Hippo pathway and study cell-fate decisions in early embryos. Lastly, we will provide exciting future perspectives on transcriptional regulatory mechanisms that modulate the activity of the Hippo pathway in preimplantation embryos to ensure robust lineage segregation.

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Cornejo, Melanie G., Vinciane Mabialah, Stephen M. Sykes, Tulasi Khandan, Cristina Lo Celso, Cécile K. Lopez, Paola Rivera-Muñoz, et al. "Crosstalk between NOTCH and AKT signaling during murine megakaryocyte lineage specification." Blood 118, no. 5 (August 4, 2011): 1264–73. http://dx.doi.org/10.1182/blood-2011-01-328567.

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Abstract The NOTCH signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. However, the molecular basis for its role at the different steps of stem cell lineage commitment is unclear. We recently identified the NOTCH signaling pathway as a positive regulator of megakaryocyte lineage specification during hematopoiesis, but the developmental pathways that allow hematopoietic stem cell differentiation into the erythro-megakaryocytic lineages remain controversial. Here, we investigated the role of downstream mediators of NOTCH during megakaryopoiesis and report crosstalk between the NOTCH and PI3K/AKT pathways. We demonstrate the inhibitory role of phosphatase with tensin homolog and Forkhead Box class O factors on megakaryopoiesis in vivo. Finally, our data annotate developmental mechanisms in the hematopoietic system that enable a decision to be made either at the hematopoietic stem cell or the committed progenitor level to commit to the megakaryocyte lineage, supporting the existence of 2 distinct developmental pathways.

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Zeddies, Sabrina, Sjoert Jansen, Franca di Summa, Sofieke Klamer, Marion Kleier, Jaap Jan Zwaginga, Marieke von Lindern, C. Ellen Van der Schoot, and Daphne C. Thijssen-Timmer. "MEIS1 Regulates Early Erythroid and Megakaryocytic Lineage Decision." Blood 118, no. 21 (November 18, 2011): 2365. http://dx.doi.org/10.1182/blood.v118.21.2365.2365.

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Abstract Abstract 2365 The transcription factor MEIS1 is essential for definitive hematopoiesis in the mouse embryo and during zebrafish development. MEIS1 deficient mice die at mid gestation, mainly due to a poorly developed HSC compartment and a reduction in myeloerythroid colony forming cells. We have previously shown by comparative transcriptional profiling of all human adult blood cell lineages that MEIS1 is specifically expressed in megakaryocytes (MK). It is however not yet known if and where MEIS1 participates in the human hematopoietic transcription factor hierarchy. We established that primary hematopoietic stem and progenitor (CD34+) cells in human bone marrow had high expression of MEIS1, which was comparable to CD34+ cells in cord blood (CB) and even higher (p<0.01) in mobilized peripheral blood (MPB). Compared to other bone marrow progenitor subsets, MEIS1 expression was highest in hematopoietic stem cells (HSC:CD34+/CD38−) and significantly reduced (p<0.01) in downstream granulocyte monocyte progenitors (GMP:CD34+/CD38+/CD110−/CD45RA+) and megakaryocyte-erythrocyte progenitors (MEP:CD34+/CD38+/CD110+/CD45RA−). We then analyzed the hematopoietic potential of CD34+ cells derived from CB or MPB, in which MEIS1 expression was silenced with short hairpins or overexpressed using lentiviral vectors. Cells were sorted for GFP expression at 48 hours after transduction and evaluated for colony forming potential. MEIS1 knockdown in human CD34+ cells resulted in a near absence of BFU-E, a 70% reduction in CFU-GM and a 25% reduction in CFU-MEG (p<0.01). When transduced CD34+ cells were cultured in suspension with EPO, SCF and IL-3 promoting differentiation towards erythroblasts or with TPO and IL-1β towards megakaryocytes, knockdown of MEIS1 significantly inhibited the proliferation of both erythroblasts and megakaryocytes (p<0.01). In addition, the expression of CD235a on erythroblasts was reduced by 60% (p<0.01) upon MEIS1 knockdown, whereas no changes were detected in the expression of CD41 on MKs. On the other hand, overexpression of MEIS1 altered lineage differentiation of human CD34+ cells without influencing the total outgrowth of colonies, inducing a 3-fold increase of BFU-E and a 2.5-fold increase in CFU-MEG at the expense of a 3-fold reduction in CFU-GM. Furthermore, since established erythroblast cultures were not affected by knockdown of MEIS1, we hypothesized that MEIS1 might regulate the erythroid/megakaryocytic lineage decision in the common myeloid progenitor (CMP). To test this hypothesis, we sorted CMPs (CD34+/CD38+/CD110−/CD45RA−), transduced the cells with MEIS1 and evaluated their colony forming potential. Indeed, overexpression of MEIS1 in CMP induced an increase in CFU-MEG and BFU-E and a striking absence of CFU-GM. When MEIS1 was overexpressed in GMP no differences were observed compared to the empty vector. In summary, MEIS1 expression in primary human progenitor cells is essential for the formation of myeloid cells, erythroblasts and megakaryocytes. However, a surplus of MEIS1 inhibits myeloid differentiation and enhances erythroid and megakaryocytic development. We therefore conclude that MEIS1 is a novel regulator for differentiation of human CMPs and that gene dosage of MEIS1 determines its lineage fate decisions. Disclosures: No relevant conflicts of interest to declare.

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VALDEZ, P., and E. ROBEY. "Notch and the CD4 Versus CD8 Lineage Decision." Cold Spring Harbor Symposia on Quantitative Biology 64 (January 1, 1999): 27–32. http://dx.doi.org/10.1101/sqb.1999.64.27.

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Taniuchi, Ichiro. "Transcriptional regulation in helper versus cytotoxic-lineage decision." Current Opinion in Immunology 21, no. 2 (April 2009): 127–32. http://dx.doi.org/10.1016/j.coi.2009.03.012.

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Akashi, Koichi. "Lymphoid Lineage Fate Decision of Hematopoietic Stem Cells." Annals of the New York Academy of Sciences 1176, no. 1 (September 2009): 18–25. http://dx.doi.org/10.1111/j.1749-6632.2009.04570.x.

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Enver, Tariq, and Sui Huang. "Mathematical Modeling of Transcriptional Regulatory Circuits Defines Cell Fate Attractors and Predicts the Genome-Scale Behaviour of Haemopoietic Progenitor Cells Undergoing a Binary Cell Fate Decision." Blood 106, no. 11 (November 16, 2005): 4219. http://dx.doi.org/10.1182/blood.v106.11.4219.4219.

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Abstract Adopting a lineage from amongst two or more options is a fundamental developmental decision in multicellular organisms. Transcription factors and their binding sites have been studied as candidate instigators of lineage. However, how the logic of gene regulatory networks translates into, for example, a binary lineage decision remains unanswered. We use mathematical modeling to understand a simple lineage decision between two hypothetical lineages A and B governed by a gene circuit containing positive auto-regulation and cross-inhibition between two regulatory factors, a and b (Fig. 1a). Experimental evidence for such a circuit is provided by the regulatory interactions of GATA-1 and PU.1 in erythroid vs. myelomonocytic lineage specification. A set of non linear ordinary differential equations describing this circuit predicts a robust generic dynamics represented in a ‘potential landscape’ (Fig. 1b, and as schematic cross section, Fig. 1c). Strikingly, the model generates three stable states or ‘attractors’ which we infer to correspond to the committed A or B lineage cells and the uncommitted bipotent A/B progenitors, which are characterized by low-level co-expression of both a and b lineage-affiliated regulators. Thus, this bipotent cell fate attractor provides, for the first time, a mathematical rationale for experimental observations of co-expression of lineage-specific regulators in uncommitted cells, a phenomenon termed ‘multi-lineage priming’. The model predicts a particular trajectory in the a/b space for bipotent cells undergoing differentiation. Specifically, lineage determination involves moving towards a region in a/b space that becomes unstable (Fig. 1c bottom) so that the two lineage-committed territories in the a/b-space directly meet (asterisk, Fig. 1b). The precipitous nature of this boundary region is predicted to afford the initiation and consolidation of a lineage decision in response to relatively modest changes in cell intrinsic or extrinsic cues. We tested these predictions through examination of global gene expression profiles of uncommitted FDCP-mix cells undergoing differentiation to erythroid (E) versus myelomonocytic (M) cell fates. Consistent with the model, differentiation down these two paths follows almost identical high-dimensional ‘trajectories’ in gene expression state space during the first 24–48h towards a characteristic, destabilized state, and only hereafter do the trajectories diverge into the attractors that represent the committed cell fates. Specifically, differentiation into myelomonocytic cells was associated with the counterintuitive transient suppression of myeloid specific PU.1, precisely as predicted by the model (Fig. 1b). In conclusion, although the mathematical model describes a small network module rather than the genome-wide gene regulatory, it captures many of the essential features of a multilineage cell differentiation hierarchy and successfully predicts the genome-scale behaviour of cells undergoing differentiation and lineage specification. Figure Figure

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de Leeuw, David C., Willemijn de van den Ancker, Fedor Denkers, Renee X. de Menezes, Theresia M. Westers, Gert J. Ossenkoppele, Arjan A. Van de Loosdrecht, and Linda Smit. "Microrna Profiling Classifies Acute Leukemias of Ambiguous Lineage As Either Acute Myeloid Leukemia or Acute Lymphoid Leukemia." Blood 120, no. 21 (November 16, 2012): 1443. http://dx.doi.org/10.1182/blood.v120.21.1443.1443.

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Abstract Abstract 1443 Introduction Classification of acute leukemia (AL) is based on commitment of the leukemic cells to either the myeloid or the lymphoid lineage. However, a small percentage of AL cases lacks immunophenotypical lineage commitment or displays features of both hematopoietic lineages. These leukemias of ambiguous lineage represent a heterogeneous category of AL that cannot be classified as either myeloid AL (AML) or lymphoid AL (ALL). This presents a major hurdle for choice of treatment, because it is unsettled whether these patients benefit from AML or ALL treatment regimens or a mixture of both. Better diagnostic tools to define the lineage of origin for these AL would be instrumental to direct therapy decision making. MicroRNAs are small single stranded RNA molecules which regulate gene expression by promoting degradation of mRNAs or repressing their translation. MicroRNA expression profiles have been shown to accurately discriminate AL of the lymphoid lineage from AL of the myeloid lineage. Here, we investigated microRNA expression profiles of leukemias of ambiguous lineage to classify them as either AML or ALL. Methods MicroRNA expression profiles of nine patients with leukemia of ambiguous lineage and eleven patients with AML, B-ALL or T-ALL were analyzed using microarray analysis. MicroRNAs differentially expressed between the myeloid and lymphoid lineage were selected using Linear Model for Microarray Analysis (LIMMA) and used for unsupervised clustering of the ambiguous lineage leukemias with the AML, B-ALL and T-ALL samples. The top five most discriminating microRNAs were selected for qRT-PCR validation in eight additional ambiguous lineage cases, five AML or ALL cases and two control cell lines. Results Unsupervised clustering analysis of the AML, B-ALL and T-ALL samples resulted in a clear separation between the myeloid and lymphoid lineages. Top differentially expressed microRNAs were miR-199b, miR-27a/b, miR-223, miR-23a, miR-221 and miR-150. When comparing leukemias of ambiguous lineage with AML, B-ALL and T-ALL using LIMMA, no clear differences were found, indicating that leukemias of ambiguous lineage are not a separate entity. Moreover, unsupervised clustering of all AL samples using the top 10 percent of most variable microRNAs resulted in clustering of leukemias of ambiguous lineage with either AML, B-ALL or T-ALL and showed comparable expression profiles. Expression analysis by qRT-PCR of the five most discriminative microRNAs on the additional samples, including leukemias of ambiguous lineage, was able to accurately assign these leukemias to the lineage of origin. Conclusion MicroRNA expression profiling of leukemias of ambiguous lineage indicated the presence of a myeloid or lymphoid lineage-specific genotype despite an indistinct immunophenotype. Analyzing microRNA expression at diagnosis to classify acute leukemias of ambiguous lineage as either AML or ALL might be instrumental to therapeutic decision making. Disclosures: No relevant conflicts of interest to declare.

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Orgogozo, Virginie, François Schweisguth, and Yohanns Bellaïche. "Binary cell death decision regulated by unequal partitioning of Numb at mitosis." Development 129, no. 20 (October 15, 2002): 4677–84. http://dx.doi.org/10.1242/dev.129.20.4677.

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An important issue in Metazoan development is to understand the mechanisms that lead to stereotyped patterns of programmed cell death. In particular, cells programmed to die may arise from asymmetric cell divisions. The mechanisms underlying such binary cell death decisions are unknown. We describe here a Drosophila sensory organ lineage that generates a single multidentritic neuron in the embryo. This lineage involves two asymmetric divisions. Following each division, one of the two daughter cells expresses the pro-apoptotic genes reaper and grim and subsequently dies. The protein Numb appears to be specifically inherited by the daughter cell that does not die. Numb is necessary and sufficient to prevent apoptosis in this lineage. Conversely, activated Notch is sufficient to trigger death in this lineage. These results show that binary cell death decision can be regulated by the unequal segregation of Numb at mitosis. Our study also indicates that regulation of programmed cell death modulates the final pattern of sensory organs in a segment-specific manner.

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Brown, Geoffrey. "Towards a New Understanding of Decision-Making by Hematopoietic Stem Cells." International Journal of Molecular Sciences 21, no. 7 (March 29, 2020): 2362. http://dx.doi.org/10.3390/ijms21072362.

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Cells within the hematopoietic stem cell compartment selectively express receptors for cytokines that have a lineage(s) specific role; they include erythropoietin, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, granulocyte/macrophage colony-stimulating factor and the ligand for the fms-like tyrosine kinase 3. These hematopoietic cytokines can instruct the lineage fate of hematopoietic stem and progenitor cells in addition to ensuring the survival and proliferation of cells that belong to a particular cell lineage(s). Expression of the receptors for macrophage colony-stimulating factor and granulocyte colony-stimulating factor is positively autoregulated and the presence of the cytokine is therefore likely to enforce a lineage bias within hematopoietic stem cells that express these receptors. In addition to the above roles, macrophage colony-stimulating factor and granulocyte/macrophage colony-stimulating factor are powerful chemoattractants. The multiple roles of some hematopoietic cytokines leads us towards modelling hematopoietic stem cell decision-making whereby these cells can ‘choose’ just one lineage fate and migrate to a niche that both reinforces the fate and guarantees the survival and expansion of cells as they develop.

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Cvejic, Ana. "Mechanisms of fate decision and lineage commitment during haematopoiesis." Immunology & Cell Biology 94, no. 3 (November 17, 2015): 230–35. http://dx.doi.org/10.1038/icb.2015.96.

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Basson, M. Albert, and Rose Zamoyska. "The CD4/CD8 lineage decision: integration of signalling pathways." Immunology Today 21, no. 10 (October 2000): 509–14. http://dx.doi.org/10.1016/s0167-5699(00)01711-4.

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Germain, Ronald N. "T-cell development and the CD4–CD8 lineage decision." Nature Reviews Immunology 2, no. 5 (May 2002): 309–22. http://dx.doi.org/10.1038/nri798.

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Dontje, Wendy, Remko Schotte, Tom Cupedo, Maho Nagasawa, Ferenc Scheeren, Ramon Gimeno, Hergen Spits, and Bianca Blom. "Delta-like1-induced Notch1 signaling regulates the human plasmacytoid dendritic cell versus T-cell lineage decision through control of GATA-3 and Spi-B." Blood 107, no. 6 (March 15, 2006): 2446–52. http://dx.doi.org/10.1182/blood-2005-05-2090.

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AbstractHuman early thymic precursors have the potential to differentiate into multiple cell lineages, including T cells and plasmacytoid dendritic cells (pDCs). This decision is guided by the induction or silencing of lineage-specific transcription factors. The ETS family member Spi-B is a key regulator of pDC development, whereas T-cell development is critically dependent on GATA-3. Here we show that triggering of the Notch1 signaling pathway by Delta-like1 controls the T/pDC lineage decision by regulating the balance between these factors. CD34+CD1a- thymic progenitor cells express Notch1, but down-regulate this receptor when differentiating into pDCs. On coculture with stromal cell lines expressing either human Delta-like1 (DL1) or Jagged1 (Jag1) Notch ligands, thymic precursors express GATA-3 and develop into CD4+CD8+TCRαβ+ T cells. On the other hand, DL1, but not Jag1, down-regulates Spi-B expression, resulting in impaired development of pDCs. The Notch1-induced block in pDC development can be relieved through the ectopic expression of Spi-B. These data indicate that DL1-induced activation of the Notch1 pathway controls the lineage commitment of early thymic precursors by altering the levels between Spi-B and GATA-3. (Blood. 2006;107:2446-2452)

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Frontelo, Maria Pilar, Deepa Manwani, Mariann Galdass, Holger Karsunky, Patrick G. Gallagher, and James J. Bieker. "Novel Role for EKLF in Megakaryocyte-Erythroid Differential Lineage Commitment." Blood 108, no. 11 (November 16, 2006): 4205. http://dx.doi.org/10.1182/blood.v108.11.4205.4205.

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Abstract Megakaryocytes and erythroid cells are thought to derive from a common progenitor. Although a number of transcriptional regulators are important for this process, they do not explain the bipotential result. We have used gain- and loss-of-function studies, expression profiling, and molecular analyses to show that EKLF, a transcription factor whose crucial role in erythroid gene regulation is well established, plays an unexpected function in the lineage decision between megakaryopoiesis and erythropoiesis. It achieves this by inhibiting the formation of megakaryocytes derived from the common megakaryocyte-erythroid precursor (MEP) cell, while at the same time stimulating erythroid differentiation. Quantitative examination of EKLF expression during hematopoiesis reveals that, unlike genes whose presence is required for establishment of both lineages, EKLF expression is uniquely down-regulated in megakaryocytes after formation of the MEP. Microarray and molecular analyses support these observations and suggest that megakaryocytic inhibition is achieved, at least in part, by EKLF repression of Fli-1 message levels. These results reveal for the first time that EKLF plays a directive role in erythroid and megakaryocyte lineage decisions prior to establishment of the red cell compartment and suggest a model for transcription factor antagonism in MEP differential lineage commitment. Tests as predicted by this model will be discussed.

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Doulatov, Sergei, Faiyaz Notta, and John E. Dick. "Clonal Analysis of the Human Hematopoietic Hierarchy Reveals An Early Lymphoid Progenitor with Extensive Monocytic Potential." Blood 114, no. 22 (November 20, 2009): 1503. http://dx.doi.org/10.1182/blood.v114.22.1503.1503.

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Abstract Abstract 1503 Poster Board I-526 The classical model of hematopoiesis posits the segregation of lymphoid and myeloid lineages as the earliest fate decision. Although the validity of this model in the mouse has recently been questioned, its status in human hematopoiesis is unclear, since little is known concerning lineage potential of human progenitors at the clonal level. We isolated and clonally mapped the developmental potential of each major progenitor class from neonatal cord blood and adult bone marrow providing the first comprehensive analysis of the human hematopoietic hierarchy. Human myeloid commitment follows the classical pattern of lineage restriction, however lymphoid development is initiated by a novel cell type, termed lympho-myeloid progenitor (LMP), which displays extensive monocytic potential. However, this myeloid capacity is lost following B- or T/NK-cell lineage commitment. The myeloid potential of LMPs is sensitive to extrinsic signals and can be directed towards differentiation into dendritic cells (DCs). Thus, human lymphoid development does not follow a rigid model of segregation of myeloid-lymphoid lineages, but proceeds through LMPs. LMPs can be massively expanded and differentiated into mature T-cells and DCs that are functionally indistinguishable from DCs derived from peripheral blood monocytes. The prospective isolation and elucidation of clonal lineage potential of human progenitors provides the basis for novel cellular therapeutics and a powerful means to uncover the cellular and molecular regulators that govern human lineage commitment. Disclosures: Dick: Roche: Research Funding; CSL Ltd: Research Funding.

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Brown, Geoffrey, Lucía Sánchez, and Isidro Sánchez-García. "Lineage Decision-Making within Normal Haematopoietic and Leukemic Stem Cells." International Journal of Molecular Sciences 21, no. 6 (March 24, 2020): 2247. http://dx.doi.org/10.3390/ijms21062247.

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To produce the wide range of blood and immune cell types, haematopoietic stem cells can “choose” directly from the entire spectrum of blood cell fate-options. Affiliation to a single cell lineage can occur at the level of the haematopoietic stem cell and these cells are therefore a mixture of some pluripotent cells and many cells with lineage signatures. Even so, haematopoietic stem cells and their progeny that have chosen a particular fate can still “change their mind” and adopt a different developmental pathway. Many of the leukaemias arise in haematopoietic stem cells with the bulk of the often partially differentiated leukaemia cells belonging to just one cell type. We argue that the reason for this is that an oncogenic insult to the genome “hard wires” leukaemia stem cells, either through development or at some stage, to one cell lineage. Unlike normal haematopoietic stem cells, oncogene-transformed leukaemia stem cells and their progeny are unable to adopt an alternative pathway.

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Agyemang, Amanda, Xianyu Zhang, Karen Laky, and B. J. Fowlkes. "Coordinate Regulation of TCR signaling, Notch, and Gata3 in T Cell Development (138.27)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 138.27. http://dx.doi.org/10.4049/jimmunol.182.supp.138.27.

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Abstract The transcription factors, Notch and Gata3, are both involved in the intrathymic development of CD4 lineage T cells. It has been proposed that Gata3 is critical in CD4 T cell maturation after lineage commitment. To the contrary, we find that disruption of the Gata3 gene re-directs a fraction of MHC II-restricted thymocytes to the CD8 lineage. Moreover, Gata3 binds regulatory regions of the ThPOK (Zbtb7b) gene in vivo and is required for the ThPOK expression that enforces CD4 lineage commitment (Nature Immunol. 9:1122). Collectively, these findings place Gata3 developmentally upstream of the CD4/CD8 lineage decision and raise the question of how Gata3 itself is regulated. Our data and that of others suggest that Gata3 expression is regulated by TCR signaling, but Gata3 can also promote TCR signaling/expression. Therefore, Gata3 may operate in a self-reinforcing feedback loop during positive selection to achieve the levels of TCR signaling required for ThPOK induction and CD4 lineage commitment. In the differentiation of peripheral Th2 cells, Gata3 transcription can be regulated by Notch. We find that Notch and Gata3 promote TCR signal transduction prior to positive selection, as well as the selection/maturation of CD4/CD8 T lineages. Thus, we have designed genetic and expression studies to investigate whether Notch regulates Gata3 in thymocytes. Intramural Research Program of the National Institute of Allergy and Infectious Diseases.

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Fuseini, Kamil, and Ishmael Kalule-Sabiti. "Lineage and Women’s Autonomy in Household Decision-making in Ghana." Journal of Human Ecology 53, no. 1 (January 2016): 29–38. http://dx.doi.org/10.1080/09709274.2016.11906953.

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Stier, Sebastian, Tao Cheng, David Dombkowski, Nadia Carlesso, and David T. Scadden. "Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome." Blood 99, no. 7 (April 1, 2002): 2369–78. http://dx.doi.org/10.1182/blood.v99.7.2369.

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Hematopoietic stem cells sequentially pass through a series of decision points affecting self-renewal or lineage-specific differentiation. Notch1 receptor is a known modulator of lineage-specific events in hematopoiesis that we assessed in the context of in vivo stem cell kinetics. Using RAG-1−/−mouse stems cells, we documented increased stem cell numbers due to decreased differentiation and enhanced stem cell self-renewal induced by Notch1. Unexpectedly, preferential lymphoid over myeloid lineage commitment was noted when differentiation occurred. Therefore, Notch1 affects 2 decision points in stem cell regulation, favoring self-renewal over differentiation and lymphoid over myeloid lineage outcome. Notch1 offers an attractive target for stem cell manipulation strategies, particularly in the context of immunodeficiency and acquired immunodeficiency syndrome.

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Taghon, Tom, Inge Van de Walle, Els Waegemans, Jelle De Medts, Greet De Smet, Magda De Smedt, Bart Vandekerckhove, et al. "Notch ligands control the human αβ/γδ lineage choice through receptor-specific induction of differential Notch signal strength. (111.29)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 111.29. http://dx.doi.org/10.4049/jimmunol.188.supp.111.29.

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Abstract Differential Notch signal strength influences the αβ versus γδ T-cell lineage decision in both mouse and human. Here, we show that the Notch ligands Delta-like-4, Jagged1 and Jagged2, differentially impact this lineage decision in human. Whereas Delta-like-4 supports both αβ and γδ T-cell development, Jagged1 induces αβ-lineage differentiation and Jagged2 primarily γδ T-cell development. Jagged2 induces the strongest Notch signal in human thymocytes as a result of interactions with both Notch1 and Notch3, whereas Delta-like-4 only binds Notch1. In agreement, Notch3 is a stronger activator of Notch target genes and only supports γδ-lineage development, whereas Notch1 is a weaker activator supporting both αβ and γδ T cell development. Blockage of Notch3 activation in Jagged2 cocultures rescues αβ-lineage differentiation, showing the importance of this interaction for driving γδ-lineage differentiation. Further analysis revealed that Jagged2-mediated Notch3 activation blocks αβ-lineage differentiation as a result of inhibition of TCR-β chain expression. Consistently, TCR-αβ T cell development is restored in Jagged2 cocultures by providing immature human T cell progenitors with a TCR-β chain. Our results show that Notch ligands control the human αβ/γδ lineage choice through receptor-specific induction of differential Notch signal strength and that Jagged2-mediated Notch3 activation drives human γδ-lineage differentiation as a result of inhibition of αβ-lineage differentiation.

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Lunardi, Andrea, Jlenia Guarnerio, Guocan Wang, Takahiro Maeda, and Pier Paolo Pandolfi. "Role of LRF/Pokemon in lineage fate decisions." Blood 121, no. 15 (April 11, 2013): 2845–53. http://dx.doi.org/10.1182/blood-2012-11-292037.

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Abstract In the human genome, 43 different genes are found that encode proteins belonging to the family of the POK (poxvirus and zinc finger and Krüppel)/ZBTB (zinc finger and broad complex, tramtrack, and bric à brac) factors. Generally considered transcriptional repressors, several of these genes play fundamental roles in cell lineage fate decision in various tissues, programming specific tasks throughout the life of the organism. Here, we focus on functions of leukemia/lymphoma-related factor/POK erythroid myeloid ontogenic factor, which is probably one of the most exciting and yet enigmatic members of the POK/ZBTB family.

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Suzuki, Harumi, Yoichi Shinkai, Lawrence G. Granger, Frederick W. Alt, Paul E. Love, and Alfred Singer. "Commitment of Immature CD4+8+ Thymocytes to the CD4 Lineage Requires CD3 Signaling but Does Not Require Expression of Clonotypic T Cell Receptor (TCR) Chains." Journal of Experimental Medicine 186, no. 1 (July 7, 1997): 17–23. http://dx.doi.org/10.1084/jem.186.1.17.

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As a consequence of positive selection in the thymus, immature CD4+8+ double-positive, [DP] thymocytes selectively terminate synthesis of one coreceptor molecule and, as a result, differentiate into either CD4+ or CD8+ T cells. The decision by individual DP thymocytes to terminate synthesis of one or the other coreceptor molecule is referred to as lineage commitment. Previously, we reported that the intrathymic signals that induced commitment to the CD4 versus CD8 T cell lineages were markedly asymmetric. Notably, CD8 commitment appeared to require lineage-specific signals, whereas CD4 commitment appeared to occur in the absence of lineage-specific signals by default. Consequently, it was unclear whether CD4 commitment, as revealed by selective termination of CD8 coreceptor synthesis, occurred in all DP thymocytes, or whether CD4 commitment occurred only in T cell receptor (TCR)–CD3-signaled DP thymocytes. Here, we report that selective termination of CD8 coreceptor synthesis does not occur in DP thymocytes spontaneously. Rather, CD4 commitment in DP thymocytes requires signals transduced by either CD3 or ζ chains, which can signal CD4 commitment even in the absence of clonotypic TCR chains.

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Semrau, Stefan, and Alexander van Oudenaarden. "Studying Lineage Decision-Making In Vitro: Emerging Concepts and Novel Tools." Annual Review of Cell and Developmental Biology 31, no. 1 (November 13, 2015): 317–45. http://dx.doi.org/10.1146/annurev-cellbio-100814-125300.

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Rothenberg, Ellen V. "Decision by committee: new light on the CD4/CD8‐lineage choice." Immunology & Cell Biology 87, no. 2 (December 16, 2008): 109–12. http://dx.doi.org/10.1038/icb.2008.100.

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Washburn, Tracy, Edina Schweighoffer, Thomas Gridley, David Chang, B. J. Fowlkes, Dragana Cado, and Ellen Robey. "Notch Activity Influences the αβ versus γδ T Cell Lineage Decision." Cell 88, no. 6 (March 1997): 833–43. http://dx.doi.org/10.1016/s0092-8674(00)81929-7.

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Naito, Taku, and Ichiro Taniuchi. "Roles of repressive epigenetic machinery in lineage decision of T cells." Immunology 139, no. 2 (April 23, 2013): 151–57. http://dx.doi.org/10.1111/imm.12058.

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Benz, Claudia, and Conrad C. Bleul. "A multipotent precursor in the thymus maps to the branching point of the T versus B lineage decision." Journal of Experimental Medicine 202, no. 1 (June 27, 2005): 21–31. http://dx.doi.org/10.1084/jem.20050146.

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Hematopoietic precursors continuously colonize the thymus where they give rise mainly to T cells, but also to B and dendritic cells. The lineage relationship between these three cell types is unclear, and it remains to be determined if precursors in the thymus are multipotent, oligopotent, or lineage restricted. Resolution of this question necessitates the determination of the clonal differentiation potential of the most immature precursors in the thymus. Using a CC chemokine receptor 9–enhanced green fluorescent protein knock-in allele like a surface marker of unknown function, we identify a multipotent precursor present in bone marrow, blood, and thymus. Single cells of this precursor give rise to T, B, and dendritic cells. A more differentiated stage of this multipotent precursor in the thymus has lost the capacity to generate B but not T, dendritic, and myeloid cells. Thus, the newly identified precursor maps to the branching point of the T versus B lineage decision in the hematopoietic lineage hierarchy.

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Sagar and Dominic Grün. "Deciphering Cell Fate Decision by Integrated Single-Cell Sequencing Analysis." Annual Review of Biomedical Data Science 3, no. 1 (July 20, 2020): 1–22. http://dx.doi.org/10.1146/annurev-biodatasci-111419-091750.

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Cellular differentiation is a common underlying feature of all multicellular organisms through which naïve cells progressively become fate restricted and develop into mature cells with specialized functions. A comprehensive understanding of the regulatory mechanisms of cell fate choices during development, regeneration, homeostasis, and disease is a central goal of modern biology. Ongoing rapid advances in single-cell biology are enabling the exploration of cell fate specification at unprecedented resolution. Here, we review single-cell RNA sequencing and sequencing of other modalities as methods to elucidate the molecular underpinnings of lineage specification. We specifically discuss how the computational tools available to reconstruct lineage trajectories, quantify cell fate bias, and perform dimensionality reduction for data visualization are providing new mechanistic insights into the process of cell fate decision. Studying cellular differentiation using single-cell genomic tools is paving the way for a detailed understanding of cellular behavior in health and disease.

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Mitnacht, Rita, Astrid Bischof, Nora Torres-Nagel, and Thomas Hünig. "Opposite CD4/CD8 Lineage Decisions of CD4+8+ Mouse and Rat Thymocytes to Equivalent Triggering Signals: Correlation with Thymic Expression of a Truncated CD8α Chain in Mice But Not Rats." Journal of Immunology 160, no. 2 (January 15, 1998): 700–707. http://dx.doi.org/10.4049/jimmunol.160.2.700.

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Abstract Unselected CD4+8+ rat thymocytes, generated in vitro from their direct precursors, are readily converted to functional TCRhigh T cells by stimulation with immobilized TCR-specific mAb plus IL-2. Lineage decision invariably occurs toward CD4−8+, regardless of the timing of TCR stimulation after entry into the CD4+8+ compartment or the concentration of TCR-specific mAb used for stimulation. CD4-specific mAb synergizes with suboptimal TCR-specific mAb in inducing T cell maturation, but lineage decision remains exclusively CD4−8+. These results contrast with those obtained in mice, in which Abs to the TCR complex were shown to promote CD4+8− T cell maturation from CD4+8+ thymocytes. Surprisingly, when rat and mouse CD4+8+ thymocytes were stimulated with PMA/ionomycin under identical conditions, the opposite lineage commitment was observed, i.e., mouse thymocytes responded with the generation of CD4+8− and rat thymocytes with the generation of CD4−8+ cells. It thus seems that CD4+8+ thymocytes of the two species respond with opposite lineage decisions to strong activating signals such as given by TCR-specific mAb or PMA/ionomycin. A possible key to this difference lies in the availability of p56lck for coreceptor-supported signaling. We show that in contrast to mouse CD4+8+ thymocytes, which express both a complete and a truncated CD8α-chain (CD8α′) unable to bind p56lck, rat thymocytes only express full-length CD8α molecules. Mice, but not rats, therefore may use CD8α′ as a “dominant negative” coreceptor chain to attenuate the CD8 signal, thereby facilitating MHC class II recognition through the higher amount of p56lck delivered, and rats may use a different mechanism for MHC class distinction during positive selection.

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Bastardo Blanco, Daniel E., Kai Yang, and Hongbo Chi. "mTORC1 signaling mediates T cell lineage choices." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 53.5. http://dx.doi.org/10.4049/jimmunol.202.supp.53.5.

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Abstract The thymus supports and guides the generation of a diverse repertoire of mature T cells from precursors derived from the bone marrow. The interaction between extrinsic factors and intrinsic signal strength governs thymocyte development, but the mechanisms linking these two aspects of T cell development remain elusive. Capitalizing on genetic deletion of RAPTOR, here we report that RAPTOR-dependent mTORC1 signaling couples microenvironmental cues with metabolic programs in orchestrating reciprocal development of two fundamentally distinct T cell lineages: αβ and γδ T cells. Loss of RAPTOR impairs αβ but promotes γδ T cell development while disrupting metabolic remodeling of oxidative and glycolytic metabolism. Mechanistically, we identify mTORC1-dependent control of reactive oxygen species (ROS) production as a key metabolic signal that, upon perturbation of redox homeostasis, impinges upon T cell fate decision. Our results establish mTORC1-driven metabolic signaling as a fundamental mechanism underlying thymocyte lineage choices.

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Brand, Marjorie. "Understanding Erythropoiesis Using Quantitative Proteomics and Single Cell Mass Cytometry." Blood 134, Supplement_1 (November 13, 2019): SCI—21—SCI—21. http://dx.doi.org/10.1182/blood-2019-121109.

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The process of erythropoiesis whereby hematopoietic stem cells (HSC) differentiate into cells with increasingly restricted potential is regulated by a network of lineage-specifying transcription factors (LS-TFs) that promote erythropoiesis while simultaneously repressing other hematopoietic lineages. While TFs that stimulate differentiation towards the erythroid lineage (such as GATA1 and KLF1/EKLF) are more abundant in erythroid progenitors and precursors, these proteins are also expressed in hematopoietic stem/progenitor cells (HSPCs) although at very low levels. This suggests that the dosage of TFs plays an important role in lineage determination. Consistent with this, previous lineage reprogramming experiments have shown that ectopic expression of the same LS-TF can give rise to distinct cell fates depending on the TF's abundance. Furthermore, a controversial model proposed that TFs belonging to competing hematopoietic lineages are co-expressed in bipotential progenitors, and that changes in their relative levels drive differentiation towards one fate or another. Taken together, this suggests that changes in LS-TFs stoichiometry may be central to cell fate choice and lineage commitment. While gene regulatory networks have been established to model the process of cell fate decision in bipotential progenitors, these network models are based on mRNA measurements and have not integrated protein levels of TFs. This is a problem as protein levels do not always correlate with mRNA levels, and as such the gene regulatory network underlying erythroid lineage determination is currently unclear. While standard proteomic approaches such as Western blot or data-dependent mass spectrometry (i.e. shotgun mass spectrometry) are useful to measure changes in the relative level of a single protein over time, these approaches do not provide information on the relative levels between several proteins in the same sample, and as such, changes in protein stoichiometry for master regulators of erythropoiesis remain mostly unknown. To address these questions and to provide a better understanding of the role and importance of quantitative changes in LS-TFs for the process of erythroid lineage commitment, we have used a combination of single cell proteomic (i.e. mass cytometry or CyTOF) and targeted mass spectrometry (i.e. SRM for selected reaction monitoring coupled with the spiking of known amounts of internal standard peptides) approaches to measure changes in protein levels of master regulators of hematopoiesis and erythropoiesis. As a model system for human erythropoiesis, we used cord-blood derived CD34+ HSPCs that are driven to differentiate along the erythroid lineage using a combination of growth factors and cytokines 1. Cells were harvested every second day from HSPCs to differentiated erythroid cells. For CyTOF analysis, cells were barcoded at each time-point, combined and stained with a cocktail of antibodies against 11 cell surface markers and 16 TFs. Clustering analysis was then used to establish a temporal trajectory of erythropoiesis. The data revealed that competing LS-TFs proteins (e.g. KLF1 a pro-erythroid factor and FLI1 a pro-megakaryocyte factor) are co-expressed in bipotential progenitors at equimolar levels. Furthermore, relative levels of KLF1 vs FLI1 change gradually as the cells progress along the erythroid trajectory. Finally, ectopic expression of FLI1 in early progenitors actively deviates cells from their preferred erythroid trajectory towards a megakaryocytic lineage 2. Thus, our results support the concept that temporally-regulated quantitative changes in TFs protein levels in individual hematopoietic progenitors are key determinants of cell fate decision in human erythropoiesis. Current studies are ongoing to identify additional pairs of LS-TFs that regulate other hematopoietic transitions. Furthermore, a dynamic gene regulatory network of erythroid lineage commitment that integrates protein and mRNA data for master regulators of hematopoiesis has been established. Giarratana MC, Kobari L, Lapillonne H, et al. Ex vivo generation of fully mature human red blood cells from hematopoietic stem cells. Nat Biotechnol. 2005;23(1):69-74. Palii CG, Cheng Q, Gillespie MA, et al. Single-Cell Proteomics Reveal that Quantitative Changes in Co-expressed Lineage-Specific Transcription Factors Determine Cell Fate. Cell Stem Cell. 2019;24(5):812-820 e815. Disclosures No relevant conflicts of interest to declare.

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Brown, Geoffrey, and Isidro Sanchez-Garcia. "Is lineage decision-making restricted during tumoral reprograming of haematopoietic stem cells?" Oncotarget 6, no. 41 (October 19, 2015): 43326–41. http://dx.doi.org/10.18632/oncotarget.6145.

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Punt, Jennifer A., Harumi Suzuki, Larry G. Granger, Susan O. Sharrow, and Alfred Singer. "Lineage Commitment in the Thymus: Only the Most Differentiated (TCRhibcl-2hi) Subset of CD4+CD8+Thymocytes Has Selectively Terminated CD4 or CD8 Synthesis." Journal of Experimental Medicine 184, no. 6 (December 1, 1996): 2091–100. http://dx.doi.org/10.1084/jem.184.6.2091.

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Lineage commitment is a developmental process by which individual CD4+CD8+ (double positive, DP) thymocytes make a decision to differentiate into either CD4+ or CD8+ T cells. However, the molecular event(s) that defines lineage commitment is controversial. We have previously proposed that lineage commitment in DP thymocytes can be molecularly defined as the selective termination of CD4 or CD8 coreceptor synthesis. The present study supports such a molecular definition by showing that termination of either CD4 or CD8 synthesis is a highly regulated event that is only evident within the most differentiated DP subset (CD5hiCD69hiTCRhibcl-2hi). In fact, essentially all cells within this DP subset actively synthesize only one coreceptor molecule. In addition, the present results identify three distinct subpopulations of DP thymocytes that define the developmental progression of the lineage commitment process and demonstrate that lineage commitment is coincident with upregulation of TCR and bcl-2. Thus, this study supports a molecular definition of lineage commitment and uniquely identifies TCRhibcl-2hi DP thymocytes as cells that are already committed to either the CD4 or CD8 T cell lineage.

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Mihajlović, Aleksandar I., and Alexander W. Bruce. "The first cell-fate decision of mouse preimplantation embryo development: integrating cell position and polarity." Open Biology 7, no. 11 (November 2017): 170210. http://dx.doi.org/10.1098/rsob.170210.

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During the first cell-fate decision of mouse preimplantation embryo development, a population of outer-residing polar cells is segregated from a second population of inner apolar cells to form two distinct cell lineages: the trophectoderm and the inner cell mass (ICM), respectively. Historically, two models have been proposed to explain how the initial differences between these two cell populations originate and ultimately define them as the two stated early blastocyst stage cell lineages. The ‘positional’ model proposes that cells acquire distinct fates based on differences in their relative position within the developing embryo, while the ‘polarity’ model proposes that the differences driving the lineage segregation arise as a consequence of the differential inheritance of factors, which exhibit polarized subcellular localizations, upon asymmetric cell divisions. Although these two models have traditionally been considered separately, a growing body of evidence, collected over recent years, suggests the existence of a large degree of compatibility. Accordingly, the main aim of this review is to summarize the major historical and more contemporarily identified events that define the first cell-fate decision and to place them in the context of both the originally proposed positional and polarity models, thus highlighting their functional complementarity in describing distinct aspects of the developmental programme underpinning the first cell-fate decision in mouse embryogenesis.

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36

Hardeland, Rüdiger. "Melatonin and the Programming of Stem Cells." International Journal of Molecular Sciences 23, no. 4 (February 10, 2022): 1971. http://dx.doi.org/10.3390/ijms23041971.

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Melatonin interacts with various types of stem cells, in multiple ways that comprise stimulation of proliferation, maintenance of stemness and self-renewal, protection of survival, and programming toward functionally different cell lineages. These various properties are frequently intertwined but may not be always jointly present. Melatonin typically stimulates proliferation and transition to the mature cell type. For all sufficiently studied stem or progenitor cells, melatonin’s signaling pathways leading to expression of respective morphogenetic factors are discussed. The focus of this article will be laid on the aspect of programming, particularly in pluripotent cells. This is especially but not exclusively the case in neural stem cells (NSCs) and mesenchymal stem cells (MSCs). Concerning developmental bifurcations, decisions are not exclusively made by melatonin alone. In MSCs, melatonin promotes adipogenesis in a Wnt (Wingless-Integration-1)-independent mode, but chondrogenesis and osteogenesis Wnt-dependently. Melatonin upregulates Wnt, but not in the adipogenic lineage. This decision seems to depend on microenvironment and epigenetic memory. The decision for chondrogenesis instead of osteogenesis, both being Wnt-dependent, seems to involve fibroblast growth factor receptor 3. Stem cell-specific differences in melatonin and Wnt receptors, and contributions of transcription factors and noncoding RNAs are outlined, as well as possibilities and the medical importance of re-programming for transdifferentiation.

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Paratore, Christian, Derk E. Goerich, Ueli Suter, Michael Wegner, and Lukas Sommer. "Survival and glial fate acquisition of neural crest cells are regulated by an interplay between the transcription factor Sox10 and extrinsic combinatorial signaling." Development 128, no. 20 (October 15, 2001): 3949–61. http://dx.doi.org/10.1242/dev.128.20.3949.

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The transcription factor Sox10 is required for proper development of various neural crest-derived cell types. Several lineages including melanocytes, autonomic and enteric neurons, and all subtypes of peripheral glia are missing in mice homozygous for Sox10 mutations. Moreover, haploinsufficiency of Sox10 results in neural crest defects that cause Waardenburg/Hirschsprung disease in humans. We provide evidence that the cellular basis to these phenotypes is likely to be a requirement for Sox10 by neural crest stem cells before lineage segregation. Cell death is increased in undifferentiated, postmigratory neural crest cells that lack Sox10, suggesting a role of Sox10 in the survival of neural crest cells. This function is mediated by neuregulin, which acts as a survival signal for postmigratory neural crest cells in a Sox10-dependent manner. Furthermore, Sox10 is required for glial fate acquisition, as the surviving mutant neural crest cells are unable to adopt a glial fate when challenged with different gliogenic conditions. In Sox10 heterozygous mutant neural crest cells, survival appears to be normal, while fate specifications are drastically affected. Thereby, the fate chosen by a mutant neural crest cell is context dependent. Our data indicate that combinatorial signaling by Sox10, extracellular factors such as neuregulin 1, and local cell-cell interactions is involved in fine-tuning lineage decisions by neural crest stem cells. Failures in fate decision processes might thus contribute to the etiology of Waardenburg/Hirschsprung disease.

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Cochrane, Shawn W., Ying Zhao, Robert S. Welner, and Xiao-Hong Sun. "Balance between Id and E proteins regulates myeloid-versus-lymphoid lineage decisions." Blood 113, no. 5 (January 29, 2009): 1016–26. http://dx.doi.org/10.1182/blood-2008-06-164996.

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Abstract Hematopoiesis consists of a series of lineage decisions controlled by specific gene expression that is regulated by transcription factors and intracellular signaling events in response to environmental cues. Here, we demonstrate that the balance between E-protein transcription factors and their inhibitors, Id proteins, is important for the myeloid-versus-lymphoid fate choice. Using Id1-GFP knockin mice, we show that transcription of the Id1 gene begins to be up-regulated at the granulocyte-macrophage progenitor stage and continues throughout myelopoiesis. Id1 expression is also stimulated by cytokines favoring myeloid differentiation. Forced expression of Id1 in multipotent progenitors promotes myeloid development and suppresses B-cell formation. Conversely, enhancing E-protein activity by expressing a variant of E47 resistant to Id-mediated inhibition prevents the myeloid cell fate while driving B-cell differentiation from lymphoid-primed multipotent progenitors. Together, these results suggest a crucial function for E proteins in the myeloid-versus-lymphoid lineage decision.

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Naito, T., and I. Taniuchi. "The network of transcription factors that underlie the CD4 versus CD8 lineage decision." International Immunology 22, no. 10 (August 22, 2010): 791–96. http://dx.doi.org/10.1093/intimm/dxq436.

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Haghverdi, Laleh, and Leif S. Ludwig. "Single-cell multi-omics and lineage tracing to dissect cell fate decision-making." Stem Cell Reports 18, no. 1 (January 2023): 13–25. http://dx.doi.org/10.1016/j.stemcr.2022.12.003.

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Philips, Rachael Laura, Jeong-Heon Lee, Krutika Gaonkar, Ji Young Chung, Sinibaldo Romero Arocha, Tamas Ordog, and Virginia Shapiro. "HDAC3 is required to suppress the CD8-lineage program in DP thymocytes for CD4-lineage T cell commitment." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 60.4. http://dx.doi.org/10.4049/jimmunol.198.supp.60.4.

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Abstract MHC-restricted CD4 and CD8 T cells are vital components of the immune system. The decision to generate CD4 or CD8 T cells occurs in the thymus. After positive selection, intermediate thymocytes downregulate CD8 to test coreceptor specificity. Thymocytes develop into CD4 T cells if they experience persistent TCR signaling, while termination of TCR signaling leads to IL-7-mediated CD8-lineage commitment via Runx3. While the general signaling and transcriptional mechanisms are known, the epigenetic mechanisms controlling error-free lineage commitment are largely unknown. We found histone deacetylase 3 (HDAC3) to be critical for generating CD4 T cells, as its deletion leads to the generation of only CD8SP cells. Introduction of an OT-II TCR transgene revealed redirection of MHC class II-restricted cells to the CD8 lineage upon HDAC3 deletion. We found evidence that HDAC3-deficient DP thymocytes are primed for the CD8-lineage, as they exhibit hyperacetylation at CD8-lineage promoting genes and show elevated expression of phosphorylated-STAT5 (pSTAT5). During lineage choice, OT-II expressing HDAC3-deficient cells inappropriately upregulate Runx3. Therefore, HDAC3 functions as a brake in DP thymocytes whose release leads to a developmental bias for CD8 T cells.

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Melichar, Heather J., Kavitha Narayan, Sandy D. Der, Yoshiki Hiraoka, Noemie Gardiol, Gregoire Jeannet, Werner Held, Cynthia A. Chambers, and Joonsoo Kang. "Regulation of γδ Versus αß T Lymphocyte Differentiation by the Transcription Factor SOX13." Science 315, no. 5809 (January 12, 2007): 230–33. http://dx.doi.org/10.1126/science.1135344.

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αβ and γδ T cells originate from a common, multipotential precursor population in the thymus, but the molecular mechanisms regulating this lineage-fate decision are unknown. We have identified Sox13 as a γδ-specific gene in the immune system. Using Sox13 transgenic mice, we showed that this transcription factor promotes γδ T cell development while opposing αβ T cell differentiation. Conversely, mice deficient in Sox13 expression exhibited impaired development of γδ T cells but not αβ T cells. One mechanism of SOX13 function is the inhibition of signaling by the developmentally important Wnt/T cell factor (TCF) pathway. Our data thus reveal a dominant pathway regulating the developmental fate of these two lineages of T lymphocytes.

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Sengupta, Ananya, Ghanshyam Upadhyay, Asif Chowdhury, and Shireen Saleque. "Regulation Of Erythro-Megakaryocytic Lineage Bifurcation By The Gfi1b Gene Target Rgs18." Blood 122, no. 21 (November 15, 2013): 1191. http://dx.doi.org/10.1182/blood.v122.21.1191.1191.

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Abstract The molecular basis for the divergence of the erythroid (red blood cell) and megakaryocyte (platelet) lineages from a common bipotent MEP (megakaryocyte-erythroid progenitor) remains undefined. We now demonstrate that Rgs18 (regulator of G protein signaling 18), a GAP (GTPase activating protein) factor and a transcriptional gene target of the Gfi1b transcriptional repressor complex, likely arbitrates this critical lineage decision downstream of Gfi1b. Rgs18 was identified in a chromatin immunoprecipitation (ChIP on chip) screen for Gfi1b/LSD1/Rcor1 targets in erythroid cells. Accordingly, Rgs18 expression was found to be up-regulated in LSD1 inhibited, and Gfi1b deficient erythroid cells confirming repression of this gene by Gfi1b and its co-factors in this lineage. In contrast, Rgs18 expression was comparable in megakaryocytic cells derived from wild type and gfi1b-/-hematopoietic progenitors indicating Gfi1b independent expression of Rgs18 in these cells. Manipulation of Rgs18 expression produced opposite effects in the erythroid and megakaryocytic lineages. Rgs18 inhibition retarded megakaryocytic differentiation while its ectopic over-expression promoted differentiation at the expense of proliferation. The reverse was observed in erythroid cells where Rgs18 inhibition produced an enhancement of differentiation while over-expression impaired erythropoiesis. Since Rgs signaling regulates the activity of downstream MAPK pathways we determined the status of these pathways in Rgs18 manipulated cells. Inhibition of Rgs18 stimulated ERK phosphorylation in megakaryocytes but diminished it in erythroid cells. In contrast, Rgs18 inhibition in erythroid cells elevated p38MAPK protein and phosphorylation levels. The opposite effects of Rgs18 manipulation on MAPK signaling in erythroid versus megakaryocytic cells while intriguing are consistent with the changes in differentiation and proliferation observed in each lineage, respectively. Although Rgs18 manipulation produced opposite effects in erythroid and megakaryocytic cells, the level and activity of this factor correlated similarly with those of the mutually antagonistic transcription factors Fli1 (Friend leukemia integration [site] 1) and KLF1/EKLF (Kruppel like factor1) in both cell types. In both lineages, Rgs18 protein levels correlated directly with Fli1, and inversely with KLF1, message levels. Since Fli1 promotes megakaryocytic, and KLF1 erythroid, development; these results demonstrate that Rgs18 promotes the emergence of megakaryocytic cells from bipotent MEPs by modulating MAPK signaling and altering Fli1/KLF1 stoichiometries. Although it is unclear why Gfi1b mediated repression of Rgs18 is erythroid specific even though the former is expressed in both lineages, these results demonstrate that repression of Rgs18 by Gfi1b in fetal liver MEPs limits megakaryopoiesis and augments erythropoiesis. However following megakaryocytic commitment, robust Gfi1b independent expression of Rgs18 drives differentiation of this lineage while continued repression of Rgs18 by Gfi1b in erythroid cells ensures their proper maturation. Disclosures: No relevant conflicts of interest to declare.

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Yin, Xinye, Ena Ladi, Shiao Wei Chan, Ou Li, Nigel Killeen, Dietmar J. Kappes, and Ellen A. Robey. "CCR7 Expression in Developing Thymocytes Is Linked to the CD4 versus CD8 Lineage Decision." Journal of Immunology 179, no. 11 (November 19, 2007): 7358–64. http://dx.doi.org/10.4049/jimmunol.179.11.7358.

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Rodríguez-Hernández, Guillermo, Sanil Bhatia, Carolina Vicente-Dueñas, Arndt Borkhardt, Julia Hauer, and Isidro Sánchez-García. "T-cell leukemogenesis is an inappropriate lineage decision-making process: implications for precision oncology." Molecular & Cellular Oncology 5, no. 4 (July 4, 2018): e1497860. http://dx.doi.org/10.1080/23723556.2018.1497860.

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Maeda, T., T. Merghoub, R. M. Hobbs, L. Dong, M. Maeda, J. Zakrzewski, M. R. M. van den Brink, et al. "Regulation of B Versus T Lymphoid Lineage Fate Decision by the Proto-Oncogene LRF." Science 316, no. 5826 (May 11, 2007): 860–66. http://dx.doi.org/10.1126/science.1140881.

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Rothenberg, Ellen V. "Negotiation of the T Lineage Fate Decision by Transcription-Factor Interplay and Microenvironmental Signals." Immunity 26, no. 6 (June 2007): 690–702. http://dx.doi.org/10.1016/j.immuni.2007.06.005.

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Zini, Roberta, Ruggiero Norfo, Francesco Ferrari, Elisa Bianchi, Simona Salati, Valentina Pennucci, Giorgia Sacchi, et al. "Valproic acid triggers erythro/megakaryocyte lineage decision through induction of GFI1B and MLLT3 expression." Experimental Hematology 40, no. 12 (December 2012): 1043–54. http://dx.doi.org/10.1016/j.exphem.2012.08.003.

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Canelles, Matilde, Melissa L. Park, Owen M. Schwartz, and B. J. Fowlkes. "The influence of the thymic environment on the CD4-versus-CD8 T lineage decision." Nature Immunology 4, no. 8 (July 13, 2003): 756–64. http://dx.doi.org/10.1038/ni953.

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Marcus, Assaf, Dinorah Friedmann-Morvinski, Eran Elinav, Tova Waks, and Zelig Eshhar. "Hierarchy of T cell lineage decision is regulated by thymic self-reactive signaling (36.45)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 36.45. http://dx.doi.org/10.4049/jimmunol.184.supp.36.45.

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Abstract During T cell development, thymic recognition of self antigens leads to negative selection of effector T cells with high TCR avidity. Similar interactions are implicated with emergence of regulatory subsets, including Tregs, NKT, and CD8αα cells. How the degree of self-reactive signaling coordinates the development of the effector and regulatory subpopulations is not fully understood. To elucidate this, we employed transgenic mice, featuring gradually increasing self-reactivity by expression of different levels of a cross-reactive tripartite chimeric receptor targeting 2,4,6-trinitrophenol (TNP). In these mice, increasing cell self-reactivity inversely correlated with effector cell numbers, and led to skewing towards CD4 phenotype, compatible with the kinetic signaling model. In parallel, coreceptor levels of expression were diminished in correlation with gradually increasing self-reactivity, reflecting coreceptor tuning. Higher levels of self-reactive signaling promoted the thymic expansion of CD8αα and NKT cells. T cells with the highest self-reactive TPCR featured defective TCR rearrangement stemming from down regulation of RAG1, RAG2 and PTα. Altogether, we demonstrate a hierarchical order in coping of the immune system with auto-reactivity. In case of weak self-reactivity, coreceptor tuning is implemented, while in stronger self-reactivity, regulatory subsets develop, as possible means of modulating dangerous autoreactive cells into protective guardians of host.

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Journal articles on the topic 'Lineage decision'

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