Pertussis toxin–sensitive G proteins regulate lymphoid lineage specification in multipotent hematopoietic progenitors

Lai, Anne Y.; Watanabe, Akiko; O'Brien, Tommy; Kondo, Motonari

doi:10.1182/blood-2009-01-201939

Cited by 17 publications

(21 citation statements)

References 41 publications

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“…Specific lymphoid niches and consequent restriction of access to M-CSF are possible explanations as to why ALPs generate so few myeloid cells in vivo [13, 43–45]. Our data are consistent with this mechanism, and justify further studies on specialized niches and cytokine gradients in vivo .…”

Section: Discussionsupporting

confidence: 84%

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ADAM17 limits the expression of CSF1R on murine hematopoietic progenitors

Becker

Walcheck

Bhattacharya

2015

Experimental Hematology

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All-lymphoid progenitors (ALPs) yield few myeloid cells in vivo, but readily generate such cells in vitro. The basis for this difference remains unknown. We hypothesized that ALPs limit responsiveness to in vivo concentrations of myeloid-promoting cytokines by reducing expression of the corresponding receptors, potentially through post-transcriptional mechanisms. Consistent with such a mechanism, ALPs express higher levels of Csf1r transcripts than their upstream precursors, yet show limited cell surface protein expression of CSF1R. ALPs and other hematopoietic progenitors deficient in ADAM17, a metalloprotease that can cleave CSF1R, display elevated cell surface CSF1R expression. Adam17−/− ALPs, however, fail to yield myeloid cells upon transplantation into irradiated recipients. Moreover, Adam17−/− ALPs yield fewer macrophages in vitro than control ALPs at high concentrations of M-CSF. Mice with hematopoietic-specific deletion of Adam17 have grossly normal numbers of myeloid and lymphoid progenitors and mature cells in vivo. These data demonstrate that ADAM17 limits CSF1R protein expression on hematopoietic progenitors, but that compensatory mechanisms prevent elevated CSF1R levels from altering lymphoid progenitor potential.

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Section: Discussionsupporting

confidence: 84%

“…One possibility is that lymphoid progenitors home to distinct "niches" in vivo in which local concentrations of myeloid cytokines are low [12, 13]. Another non-mutually exclusive possibility is that ALPs reduce the expression of myeloid cytokine receptors such that they are unresponsive to the in vivo concentrations of such factors.…”

Section: Introductionmentioning

confidence: 99%

ADAM17 limits the expression of CSF1R on murine hematopoietic progenitors

Becker

Walcheck

Bhattacharya

2015

Experimental Hematology

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“…Additional resolution and tracking of short term repopulating HSC to ELP was made possible by staining for the VCAM-1 adhesion molecule (16). RAG-1 + ELP have a much lower cloning efficiency in Methocel cultures with myeloid supporting growth factors than the otherwise similar RAG-1 − cohort (9, 31, 32). This suggests that they have initiated the process of lymphopoiesis, but not completely lost other differentiation options.…”

Section: Discussionmentioning

confidence: 84%

Asynchronous RAG-1 Expression during B Lymphopoiesis

Welner

Esplin

Garrett

et al. 2009

The Journal of Immunology

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Changes in cell surface markers and patterns of gene expression are commonly used to construct sequences of events in hematopoiesis. However, the order may not be as rigid as once thought and it is unclear which changes represent the best milestones of differentiation. We developed a fate-mapping model where cells with a history of RAG-1 expression are permanently marked by red fluorescence. This approach is valuable for appreciating lymphoid-lineage relationships without need for irradiation and transplantation. Hematopoietic stem cells (HSC) as well as myeloid and dendritic cell progenitors were unlabeled. Also as expected, most previously identified RAG-1+ early lymphoid progenitors in bone marrow and all lymphoid-affiliated cells were marked. Of particular interest, there was heterogeneity among canonical common lymphoid progenitors (CLP) in bone marrow. Labeled CLP expressed slightly higher levels of IL-7Rα, displayed somewhat less c-Kit, and generated CD19+ lymphocytes faster than the unlabeled CLP. Furthermore, CLP with a history of RAG-1 expression were much less likely to generate dendritic and NK cells. The RAG-1-marked CLP were lineage stable even when exposed to LPS, while unlabeled CLP were redirected to become dendritic cells in response to this TLR4 ligand. These findings indicate that essential events in B lymphopoiesis are not tightly synchronized. Some progenitors with increased probability of becoming lymphocytes express RAG-1 while still part of the lineage marker-negative Sca-1+c-Kithigh (LSK) fraction. Other progenitors first activate this locus after c-Kit levels have diminished and cell surface IL-7 receptors are detectable.

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“…It is also not completely clear yet what the regulatory difference is that explains these differences in myeloid potential, as lymphomyeloid bifunctional regulators like PU.1 and Flt3 (see below) seem to be expressed similarly in both. To some extent, the ability of cells to manifest myeloid potential is a function of the signaling environment, as Toll-like receptor signaling or alterations in G-protein coupled receptor signals can drive even the most restricted CLP to a nonlymphoid fate (57, 58). An obvious difference between LMPP and CLP has to do with the relative levels of growth factor receptors IL-7R and Kit they express on their surfaces.…”

Section: Developmental Paths and Choicesmentioning

confidence: 99%

Transcriptional Control of Early T and B Cell Developmental Choices

Rothenberg

2014

Annu. Rev. Immunol.

181

177

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T and B cells share a common somatic gene rearrangement mechanism for assembling the genes that code for their antigen receptors and developmental pathways with many parallels. Shared usage of basic helix-loop-helix E proteins as transcriptional drivers underlies these common features. However, the transcription factor networks in which these E proteins are embedded are different both in membership and in architecture for T and B cell gene regulatory programs. These differences permit lineage commitment decisions to be made in different hierarchical orders. Furthermore, in a contrast to B-cell gene networks, the T-cell gene network architecture for effector differentiation is sufficiently modular so that E protein inputs can be removed. Complete “T-cell-like” effector differentiation can proceed without T-cell receptor rearrangement or selection when E proteins are neutralized, yielding natural killer and other innate lymphoid cells.

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Pertussis toxin–sensitive G proteins regulate lymphoid lineage specification in multipotent hematopoietic progenitors

Cited by 17 publications

References 41 publications

ADAM17 limits the expression of CSF1R on murine hematopoietic progenitors

ADAM17 limits the expression of CSF1R on murine hematopoietic progenitors

Asynchronous RAG-1 Expression during B Lymphopoiesis

Transcriptional Control of Early T and B Cell Developmental Choices

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