Fig. 4.
Fig. 4. A model for Notch function in hematopoiesis, showing its role in mediating cell fate decisions through cell-cell interactions and transcriptional regulation. (A) Cellular interactions and effects of Notch signaling in different hematopoietic microenvironments, showing the influence of Notch on hematopoietic cells of different lineages and at different stages of maturation. Each compartment is used to emphasize particular features of Notch signaling that are also applicable to the other compartments. In the progenitor compartment (top panel), Notch signaling occurs between stromal cells and hematopoietic progenitors and between equivalent or nonequivalent hematopoietic cells. Hematopoietic progenitors express multiple Notch molecules (depicted as Notch1 and 2) and DSL ligands. Stromal cells express DSL ligands, including Jagged and Delta. In the context of various cytokines, progenitors are induced to differentiate. Notch signaling regulates the response of progenitors to cytokine stimulation, permitting some to differentiate and others to self-renew. Cells expressing more Notch are inhibited from differentiating and thus maintain a pool of uncommitted progenitors. Cells expressing less escape from the Notch signal and undergo the next step in differentiation. Commitment to the lymphoid or myeloid lineage depends on specific cytokines and the relative activities of Notch1 and 2. Increased Notch1 activity inhibits myeloid differentiation and thus favors the lymphoid pathway; however, for lymphoid commitment, progenitors must also express less Notch2 than their neighbors (increased Notch1 and 2 results in self-renewal). Myeloid differentiation is similarly favored by increased Notch2 expression (which inhibits lymphoid differentiation) and permitted by relatively low levels of Notch1. At the next step, lymphoid and myeloid precursors again either differentiate or self-renew: those expressing less Notch continue to differentiate, whereas those expressing more self-renew at this stage of maturation. In the myeloid compartment (lower left), precursors express both Notch1 and 2 and the effects on differentiation are cytokine-specific, as shown by granulocytic differentiation in response to G-CSF and GM-CSF. Either activation of Notch1 in the presence of G-CSF or activation of Notch2 in the presence of GM-CSF results in inhibition of differentiation and self-renewal of progenitors. These progenitors remain competent to adopt alternative fates in response to subsequent signals. In the absence of Notch1 or 2 activity or in the context of different cytokines (eg, GM-CSF for Notch1 or G-CSF for Notch2), myeloid progenitors differentiate to produce mature granulocytes. In the lymphoid compartment (lower right), Notch signaling involves interactions of thymocytes with each other and with thymic epithelial cells. When induced to differentiate, immature CD4−CD8− thymocytes expressing more Notch1 self-renew, whereas those expressing less undergo the next step in T-cell maturation. At this next step, in the context of a productive TCR rearrangement, CD4−CD8− precursors expressing less Notch adopt the primary γδ T-cell fate; those expressing more Notch fail to adopt the γδ cell fate, subsequently express both CD4 and CD8, and adopt the alternative β T-cell fate. These CD4+CD8+ β precursors, in turn, can either develop either as mature CD4 or CD8 T cells. Cells expressing less Notch adopt the primary CD4 cell fate, normally in association with class II MCH molecules. Development of CD8 T cells generally requires MHC class I ligation, and Notch expression in this context permits cells to adopt the CD8 cell fate. However, expression of high levels of Notch in the presence of MHC class II molecules will also permit CD8 development, while preventing cells from adopting the usual CD4 fate in this context. (B) Distinct intracellular interactions result in cytokine-specific effects of Notch1 and 2 on myeloid differentiation. The activated intracellular Notch molecule includes the cdc10 repeats, which are necessary for Notch function, and the NCR region, which confers cytokine specificity on the Notch1 and 2 molecules. In an inactive conformation, the cdc10 domain is masked and therefore unable to participate in molecular interactions required for Notch activity. Stimulation by G-CSF induces signal transduction through a pathway that includes molecule X, which can interact with the NCR domain of Notch1, but not Notch2. The interaction of X with Notch1 results in unmasking of the cdc10 repeats and facilitates the interaction of Notch1 with nuclear factors. The result is transcriptional suppression of genes that would otherwise be activated in response to G-CSF. Because the Notch2 NCR cannot interact with X, the cdc10 domain remains masked, Notch2 remains inactive, and transcriptional activation of G-CSF–induced genes results in cellular differentiation. GM-CSF signals through a different pathway, inducing molecule Y, which can interact with the NCR domain of Notch2, but not Notch1. Thus, in the context of GM-CSF stimulation, Notch2 is active (the cdc10 domain is unmasked) and inhibits transcription of GM-CSF–induced genes. In contrast, in the presence of GM-CSF, Notch1 remains inactive, lineage-specific gene transcription is permitted, and cells differentiate.

A model for Notch function in hematopoiesis, showing its role in mediating cell fate decisions through cell-cell interactions and transcriptional regulation. (A) Cellular interactions and effects of Notch signaling in different hematopoietic microenvironments, showing the influence of Notch on hematopoietic cells of different lineages and at different stages of maturation. Each compartment is used to emphasize particular features of Notch signaling that are also applicable to the other compartments. In the progenitor compartment (top panel), Notch signaling occurs between stromal cells and hematopoietic progenitors and between equivalent or nonequivalent hematopoietic cells. Hematopoietic progenitors express multiple Notch molecules (depicted as Notch1 and 2) and DSL ligands. Stromal cells express DSL ligands, including Jagged and Delta. In the context of various cytokines, progenitors are induced to differentiate. Notch signaling regulates the response of progenitors to cytokine stimulation, permitting some to differentiate and others to self-renew. Cells expressing more Notch are inhibited from differentiating and thus maintain a pool of uncommitted progenitors. Cells expressing less escape from the Notch signal and undergo the next step in differentiation. Commitment to the lymphoid or myeloid lineage depends on specific cytokines and the relative activities of Notch1 and 2. Increased Notch1 activity inhibits myeloid differentiation and thus favors the lymphoid pathway; however, for lymphoid commitment, progenitors must also express less Notch2 than their neighbors (increased Notch1 and 2 results in self-renewal). Myeloid differentiation is similarly favored by increased Notch2 expression (which inhibits lymphoid differentiation) and permitted by relatively low levels of Notch1. At the next step, lymphoid and myeloid precursors again either differentiate or self-renew: those expressing less Notch continue to differentiate, whereas those expressing more self-renew at this stage of maturation. In the myeloid compartment (lower left), precursors express both Notch1 and 2 and the effects on differentiation are cytokine-specific, as shown by granulocytic differentiation in response to G-CSF and GM-CSF. Either activation of Notch1 in the presence of G-CSF or activation of Notch2 in the presence of GM-CSF results in inhibition of differentiation and self-renewal of progenitors. These progenitors remain competent to adopt alternative fates in response to subsequent signals. In the absence of Notch1 or 2 activity or in the context of different cytokines (eg, GM-CSF for Notch1 or G-CSF for Notch2), myeloid progenitors differentiate to produce mature granulocytes. In the lymphoid compartment (lower right), Notch signaling involves interactions of thymocytes with each other and with thymic epithelial cells. When induced to differentiate, immature CD4−CD8− thymocytes expressing more Notch1 self-renew, whereas those expressing less undergo the next step in T-cell maturation. At this next step, in the context of a productive TCR rearrangement, CD4−CD8− precursors expressing less Notch adopt the primary γδ T-cell fate; those expressing more Notch fail to adopt the γδ cell fate, subsequently express both CD4 and CD8, and adopt the alternative β T-cell fate. These CD4+CD8+ β precursors, in turn, can either develop either as mature CD4 or CD8 T cells. Cells expressing less Notch adopt the primary CD4 cell fate, normally in association with class II MCH molecules. Development of CD8 T cells generally requires MHC class I ligation, and Notch expression in this context permits cells to adopt the CD8 cell fate. However, expression of high levels of Notch in the presence of MHC class II molecules will also permit CD8 development, while preventing cells from adopting the usual CD4 fate in this context. (B) Distinct intracellular interactions result in cytokine-specific effects of Notch1 and 2 on myeloid differentiation. The activated intracellular Notch molecule includes the cdc10 repeats, which are necessary for Notch function, and the NCR region, which confers cytokine specificity on the Notch1 and 2 molecules. In an inactive conformation, the cdc10 domain is masked and therefore unable to participate in molecular interactions required for Notch activity. Stimulation by G-CSF induces signal transduction through a pathway that includes molecule X, which can interact with the NCR domain of Notch1, but not Notch2. The interaction of X with Notch1 results in unmasking of the cdc10 repeats and facilitates the interaction of Notch1 with nuclear factors. The result is transcriptional suppression of genes that would otherwise be activated in response to G-CSF. Because the Notch2 NCR cannot interact with X, the cdc10 domain remains masked, Notch2 remains inactive, and transcriptional activation of G-CSF–induced genes results in cellular differentiation. GM-CSF signals through a different pathway, inducing molecule Y, which can interact with the NCR domain of Notch2, but not Notch1. Thus, in the context of GM-CSF stimulation, Notch2 is active (the cdc10 domain is unmasked) and inhibits transcription of GM-CSF–induced genes. In contrast, in the presence of GM-CSF, Notch1 remains inactive, lineage-specific gene transcription is permitted, and cells differentiate.

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