GO:0035603 fibroblast growth factor receptor signaling pathway involved in hemopoiesis: Hematopoietic Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0035603 describes the series of molecular signals generated when a fibroblast growth factor receptor (FGFR) binds a physiological ligand and contributes to hemopoiesis.
• FGFR signaling intersects with cytokine and Notch pathways to control myeloid and megakaryocytic differentiation [1,5].
• Phospholipase C gamma 1 (PLCG1) is a key downstream effector in primitive hematopoiesis during zebrafish development.
• Hemangioblast and lymph-gland hematopoiesis models in Drosophila reveal conserved FGFR-related mechanisms.
• Dysregulation of FGFR signaling is implicated in leukemias and other hematopoietic malignancies.
• CRISPR knockout, point mutation, knock-in, and overexpression models enable functional dissection of this pathway.
Description
Fibroblast growth factor receptor (FGFR) signaling is a conserved molecular cascade that regulates diverse developmental and homeostatic processes. GO:0035603, fibroblast growth factor receptor signaling pathway involved in hemopoiesis, specifically refers to the series of molecular signals generated as a consequence of an FGFR binding to one of its physiological ligands, which contributes to hemopoiesis. This term captures the intersection of growth factor signaling with blood cell formation, a process essential for understanding both normal hematopoiesis and hematopoietic disorders [1,5]. Researchers study this pathway because it modulates the differentiation, proliferation, and survival of hematopoietic stem and progenitor cells, and its dysregulation is linked to leukemias and other blood diseases. The pathway is also conserved across species, with evidence from zebrafish and Drosophila highlighting its role in primitive hematopoiesis and hemangioblast development [6,8]. Understanding GO:0035603 provides a framework for investigating how extracellular cues from FGF ligands are translated into transcriptional programs that drive blood cell fate decisions [1,5].
fibroblast growth factor receptor signaling pathway involved in hemopoiesis At A Glance
| GO ID | GO:0035603 |
|---|---|
| GO term | fibroblast growth factor receptor signaling pathway involved in hemopoiesis |
| Ontology | biological_process |
| Synonym | FGF receptor signaling pathway involved in hematopoiesis; FGFR signaling pathway involved in hematopoiesis; fibroblast growth factor receptor signaling pathway involved in hematopoiesis; fibroblast growth factor receptor signalling pathway involved in hemopoiesis |
| Major function | Transduces FGF ligand signals through FGFRs to regulate hemopoiesis, including hematopoietic stem cell maintenance, myeloid differentiation, and megakaryocytopoiesis [1,5]. |
| Key downstream effectors | Phospholipase C gamma 1 (PLCG1), Notch signaling components, and cytokine-independent megakaryocytopoiesis pathways [1,5,6]. |
| Related processes | Primitive hematopoiesis, hemangioblast development, and lymph-gland hematopoiesis in model organisms [6,8]. |
| Disease relevance | Leukemias, myeloproliferative disorders, and other hematopoietic malignancies. |
What Is GO:0035603?
GO:0035603 is defined as the series of molecular signals generated as a consequence of a fibroblast growth factor receptor binding to one of its physiological ligands, which contributes to hemopoiesis. In simpler terms, it is the specific branch of FGFR signaling that is dedicated to the formation and development of blood cells. This process includes ligand-receptor interaction, receptor activation, and downstream intracellular signaling events that ultimately influence hematopoietic cell differentiation, proliferation, and survival.
Why Is fibroblast growth factor receptor signaling pathway involved in hemopoiesis Important in Cell Biology?
GO:0035603 is important because it defines a specific signaling axis that links fibroblast growth factor receptor activity to the production of blood cells. This pathway is critical for normal hematopoietic development and its dysregulation can lead to hematological malignancies such as leukemias. Understanding the molecular players and regulatory mechanisms of this pathway provides insights into how growth factor signals are integrated with cytokine and Notch signaling to control cell fate decisions [1,5]. Moreover, model organisms like zebrafish and Drosophila have been instrumental in revealing conserved functions of FGFR signaling in primitive hematopoiesis and hemangioblast formation [6,8].
• Regulates hematopoietic stem cell maintenance and differentiation.
• Controls megakaryocytopoiesis and platelet production.
• Interacts with Notch signaling to promote myeloid differentiation.
• Involves PLCG1 as a key effector in primitive hematopoiesis.
• Conserved from Drosophila to mammals in hemangioblast development.
• Dysregulation is associated with leukemias and myeloproliferative neoplasms.
• Provides targets for therapeutic intervention in blood disorders.
• Serves as a paradigm for growth factor signaling in stem cell biology.
• Enables cross-species comparative studies of hematopoiesis [6,8].
• Facilitates development of CRISPR-based disease models.
What Happens During fibroblast growth factor receptor signaling pathway involved in hemopoiesis?
Ligand Binding and Receptor Activation
In simple terms: FGF ligands bind to FGFRs on the cell surface, causing the receptors to pair up and activate.
The pathway begins when a fibroblast growth factor (FGF) ligand binds to its cognate FGFR on the surface of hematopoietic cells or their progenitors. This binding induces receptor dimerization and autophosphorylation of intracellular tyrosine kinase domains, creating docking sites for downstream signaling proteins. This activation step is a prerequisite for the propagation of signals that contribute to hemopoiesis.
Downstream Signaling Cascades
In simple terms: Activated FGFRs trigger a relay of proteins inside the cell that carry the signal to the nucleus.
Once activated, FGFRs phosphorylate adaptor proteins and enzymes such as phospholipase C gamma 1 (PLCG1), which hydrolyzes PIP2 to generate IP3 and DAG, leading to calcium release and PKC activation. These signals are integrated with other pathways, including the Notch signaling cascade via RBP-J, to promote myeloid differentiation. The ultimate outcome is altered gene expression that drives hematopoietic cell fate decisions [1,5].
Integration with Cytokine Signaling
In simple terms: FGFR signals cooperate with cytokines like thrombopoietin to control blood cell production.
FGFR signaling intersects with cytokine pathways to regulate megakaryocytopoiesis. For example, thrombopoietin (TPO)-independent megakaryocytopoiesis can be driven by alternative signaling mechanisms that may involve FGFR activation. Interleukin-11 and its receptor also participate in hematopoietic regulation, and cross-talk between FGFR and cytokine receptors fine-tunes the hematopoietic output.
Role in Primitive and Definitive Hematopoiesis
In simple terms: FGFR signaling is important both in early embryonic blood formation and in adult blood production.
In zebrafish, PLCG1 is required for primitive hematopoiesis, demonstrating a conserved role for FGFR downstream effectors in early blood development. In Drosophila, evidence for a hemangioblast and similarities between lymph-gland hematopoiesis and mammalian aorta-gonadal-mesonephros mesoderm suggest that FGFR-related mechanisms are evolutionarily ancient. These findings highlight the dual role of FGFR signaling in both primitive and definitive hematopoiesis.
Regulation by Notch and Other Pathways
In simple terms: Other signaling pathways can turn FGFR signals up or down to balance blood cell formation.
Notch signaling via RBP-J promotes myeloid differentiation and can modulate FGFR pathway activity. Additionally, macrophage differentiation and function in health and disease are influenced by growth factor signaling, including FGFs. The interplay between FGFR, Notch, and cytokine signaling ensures proper hematopoietic homeostasis.
Key Genes Involved in GO:0035603 fibroblast growth factor receptor signaling pathway involved in hemopoiesis
The following genes and proteins are key components or regulators of the fibroblast growth factor receptor signaling pathway involved in hemopoiesis (GO:0035603), based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| FGFR1 | Fibroblast growth factor receptor 1; binds FGF ligands and initiates signaling | Implicated in leukemias and hematopoietic malignancies |
| FGFR2 | Fibroblast growth factor receptor 2; mediates FGF signaling in hematopoietic cells | Potential target in myeloproliferative disorders |
| PLCG1 | Phospholipase C gamma 1; downstream effector of FGFR signaling | Required for primitive hematopoiesis in zebrafish |
| RBP-J | Notch signaling mediator; interacts with FGFR pathway | Promotes myeloid differentiation |
| TPO | Thrombopoietin; cytokine regulating megakaryocytopoiesis | TPO-independent megakaryocytopoiesis may involve FGFR |
| IL11 | Interleukin-11; cytokine with hematopoietic functions | Interleukin-11 and its receptor regulate hematopoiesis |
| FLT3 | FMS-like tyrosine kinase 3; receptor tyrosine kinase in leukemic cells | Expressed in leukemias; potential cross-talk with FGFR |
| CSF1R | Macrophage colony-stimulating factor receptor; regulates macrophage differentiation | Macrophage differentiation and function in health and disease |
| FGF1 | Fibroblast growth factor 1; ligand for FGFRs | Prototype ligand for FGFR signaling |
| FGF2 | Fibroblast growth factor 2; ligand for FGFRs | Regulates hematopoietic cell proliferation |
| FGF4 | Fibroblast growth factor 4; ligand for FGFRs | Potential role in hematopoietic development |
| FGF8 | Fibroblast growth factor 8; ligand for FGFRs | Involved in developmental hematopoiesis |
| SPHK1 | Sphingosine kinase 1; produces S1P involved in endothelial chemotaxis | Potential mediator of hematopoietic angiogenesis |
| S1PR1 | Sphingosine-1-phosphate receptor 1; regulates endothelial barrier function | May modulate hematopoietic niche |
| LPA | Lysophosphatidic acid; lipid mediator of endothelial barrier function | Potential mediator of hematopoietic angiogenesis |
| NOTCH1 | Notch receptor 1; interacts with FGFR signaling | Promotes myeloid differentiation via RBP-J |
| GATA1 | Transcription factor essential for erythropoiesis and megakaryopoiesis | Downstream target of hematopoietic signaling |
| RUNX1 | Transcription factor critical for hematopoietic stem cell emergence | Key regulator of hemopoiesis |
How Is fibroblast growth factor receptor signaling pathway involved in hemopoiesis Regulated?
The fibroblast growth factor receptor signaling pathway involved in hemopoiesis is regulated at multiple levels. Receptor availability and ligand affinity are controlled by expression patterns of FGFs and FGFRs. Downstream effectors such as PLCG1 are modulated by calcium and PKC feedback loops. Cross-talk with Notch signaling via RBP-J provides an additional layer of regulation, promoting myeloid differentiation. Cytokine signaling, including thrombopoietin and interleukin-11, can synergize or antagonize FGFR signals to fine-tune hematopoietic output [1,2]. Additionally, lipid mediators such as sphingosine-1-phosphate and lysophosphatidic acid can influence the hematopoietic microenvironment and angiogenesis.
fibroblast growth factor receptor signaling pathway involved in hemopoiesis and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| FGFR1 | Leukemia, myeloproliferative neoplasms | Knockout or point-mutation in hematopoietic cell lines |
| PLCG1 | Primitive hematopoiesis defects | Zebrafish knockout or knockdown |
| RBP-J | Myeloid differentiation disorders | Conditional knockout in mouse hematopoietic cells |
| FLT3 | Acute myeloid leukemia | Overexpression or point mutation in leukemic cells |
| TPO | Thrombocytopenia, megakaryocytic disorders | Knockout mouse models |
Leukemias and Hematopoietic Malignancies
Dysregulated FGFR signaling has been implicated in leukemias. FLT3 receptor expression and response to FLT3 ligand by leukemic cells highlight the importance of receptor tyrosine kinase signaling in leukemia pathogenesis. Aberrant activation of FGFR pathways may contribute to leukemic cell proliferation and survival, making components of GO:0035603 potential therapeutic targets.
Myeloproliferative Disorders and Megakaryocytopoiesis
TPO-independent megakaryocytopoiesis suggests that alternative signaling pathways, possibly involving FGFR, can drive platelet production under pathological conditions. Interleukin-11 and its receptor also play roles in megakaryocytopoiesis, and their dysregulation may contribute to myeloproliferative disorders.
Macrophage Differentiation and Immune Disorders
Macrophage differentiation and function in health and disease are influenced by growth factor signaling, including FGFs. Defects in FGFR signaling could impair macrophage-mediated immune responses, linking GO:0035603 to inflammatory and immune disorders.
Developmental Hematopoietic Defects
In zebrafish, loss of PLCG1, a downstream effector of FGFR signaling, impairs primitive hematopoiesis. In Drosophila, disruption of hemangioblast development affects lymph-gland hematopoiesis, suggesting that FGFR-related pathways are critical for developmental hematopoiesis. These findings imply that mutations in GO:0035603 components could cause congenital hematopoietic defects.
From fibroblast growth factor receptor signaling pathway involved in hemopoiesis-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does FGFR1 drive leukemic cell proliferation? | FGFR1 knockout in leukemia cell lines |
| What is the role of PLCG1 in primitive hematopoiesis? | Zebrafish plcγ1 knockout or morpholino knockdown |
| How does RBP-J mediate Notch-FGFR cross-talk? | Conditional RBP-J knockout in mouse hematopoietic stem cells |
| Can TPO-independent megakaryocytopoiesis be driven by FGFR activation? | Knock-in of constitutively active FGFR in megakaryocyte progenitors |
| What is the function of FLT3 in leukemic cells? | FLT3 overexpression or point mutation in hematopoietic cell lines |
| Is there a conserved hemangioblast mechanism? | Drosophila genetic knockout of FGFR pathway components |
How to Study the fibroblast growth factor receptor signaling pathway involved in hemopoiesis Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global gene expression changes | Identify downstream targets of FGFR signaling |
| Phosphoproteomics | Phosphorylation events | Map signaling cascades downstream of FGFR |
| Flow cytometry | Cell surface markers and differentiation states | Quantify hematopoietic populations [1,5] |
| CRISPR-Cas9 knockout | Gene function loss | Study essential genes in hemopoiesis |
| CRISPR point mutation | Specific amino acid changes | Model disease-associated mutations |
| CRISPR knock-in | Tagged or reporter gene insertion | Track protein localization and interactions |
| Overexpression | Gain-of-function effects | Assess oncogenic potential of FGFR mutants |
Transcriptomic Profiling (RNA-seq)
RNA sequencing can identify global gene expression changes upon modulation of FGFR signaling in hematopoietic cells. This method reveals downstream targets and pathways that contribute to hemopoiesis, such as Notch and cytokine signaling components.
Phosphoproteomics
Phosphoproteomic analysis can map the phosphorylation events downstream of FGFR activation, identifying key effectors like PLCG1 and other signaling intermediates. This approach provides a system-wide view of the signaling network involved in hemopoiesis.
Flow Cytometry and Cell Sorting
Flow cytometry allows quantification of hematopoietic cell populations and assessment of differentiation states upon FGFR pathway manipulation. It is essential for evaluating changes in myeloid, megakaryocytic, and erythroid lineages [1,5].
CRISPR-Cas9 Genome Editing
CRISPR-Cas9 enables precise knockout, point mutation, or knock-in of genes in the FGFR pathway to study their function in hemopoiesis. This method is powerful for creating isogenic models to dissect causal roles.
How CRISPR Can Be Used to Study GO:0035603 fibroblast growth factor receptor signaling pathway involved in hemopoiesis
Knockout
CRISPR knockout of FGFR pathway genes, such as FGFR1 or PLCG1, can abolish signaling and reveal their requirement for hemopoiesis. For example, knocking out PLCG1 in zebrafish impairs primitive hematopoiesis. In mammalian cells, knockout of FGFR1 can reduce leukemic cell proliferation.
Point Mutation
Point mutations can be introduced to model specific activating or inactivating mutations found in hematopoietic malignancies. For instance, FLT3 point mutations are common in acute myeloid leukemia and can be recapitulated using CRISPR to study drug resistance.
Knock-in
Knock-in of reporter genes or epitope tags allows visualization and biochemical analysis of FGFR pathway components in hematopoietic cells. This approach can be used to track receptor localization or to introduce disease-relevant mutations.
Overexpression
Overexpression of FGF ligands or constitutively active FGFRs can drive hematopoietic cell proliferation and transformation. This is useful for modeling gain-of-function mutations in leukemias and for screening therapeutic inhibitors.
How EDITGENE Supports fibroblast growth factor receptor signaling pathway involved in hemopoiesis Research
Researchers studying fibroblast growth factor receptor signaling pathway involved in hemopoiesis-related genes often need to determine whether a candidate gene is causally involved in hematopoietic development or disease. EDITGENE provides a comprehensive suite of CRISPR-based services to enable precise functional interrogation of these genes in relevant cell models.
Contact EDITGENE today to design your custom CRISPR model for fibroblast growth factor receptor signaling pathway involved in hemopoiesis research.
Frequently Asked Questions About fibroblast growth factor receptor signaling pathway involved in hemopoiesis
What is GO:0035603?
GO:0035603 is the Gene Ontology term for the fibroblast growth factor receptor signaling pathway involved in hemopoiesis, describing the molecular signals from FGFR binding to its ligands that contribute to blood cell formation.
What genes are involved in fibroblast growth factor receptor signaling pathway involved in hemopoiesis?
Key genes include FGFR1, FGFR2, PLCG1, RBP-J, TPO, IL11, FLT3, and others that mediate or regulate the pathway [1,2,3,5,6].
How does FGFR signaling contribute to hemopoiesis?
FGFR signaling activates downstream cascades, such as PLCG1 and Notch, that control hematopoietic stem cell differentiation, proliferation, and survival [1,5,6].
What diseases are associated with FGFR signaling in hemopoiesis?
Dysregulation is linked to leukemias, myeloproliferative disorders, and developmental hematopoietic defects [1,3,6].
What model organisms are used to study GO:0035603?
Zebrafish and Drosophila are valuable models for studying primitive hematopoiesis and hemangioblast development [6,8].
How can CRISPR be used to study this pathway?
CRISPR knockout, point mutation, knock-in, and overexpression can dissect gene function and model disease mutations in hematopoietic cells.
What is the role of PLCG1 in hemopoiesis?
PLCG1 is a downstream effector of FGFR signaling and is required for primitive hematopoiesis in zebrafish.
How does Notch signaling interact with FGFR in hemopoiesis?
Notch signaling via RBP-J promotes myeloid differentiation and can modulate FGFR pathway activity.
What is TPO-independent megakaryocytopoiesis?
It is the production of megakaryocytes without thrombopoietin, potentially driven by alternative pathways such as FGFR signaling.
What experimental methods are used to study FGFR signaling in hemopoiesis?
Common methods include RNA-seq, phosphoproteomics, flow cytometry, and CRISPR-Cas9 genome editing [3,5,6].
Conclusion
GO:0035603, fibroblast growth factor receptor signaling pathway involved in hemopoiesis, represents a critical intersection of growth factor signaling and blood cell development. Understanding its molecular components and regulatory mechanisms provides insights into normal hematopoiesis and diseases such as leukemia. CRISPR-based models and advanced omics technologies are powerful tools to dissect this pathway and identify therapeutic targets. EDITGENE offers comprehensive services to support researchers in this endeavor.
References
- 1. Zheng C et al.. 2008. TPO-independent megakaryocytopoiesis.. Crit Rev Oncol Hematol 65(3):212-22 PMID: 18093840
- 2. Yang YC et al.. 1992. Interleukin-11 and its receptor.. Biofactors 4(1):15-21 PMID: 1292471
- 3. Drexler HG. 1996. Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells.. Leukemia 10(4):588-99 PMID: 8618433
- 4. Naito M. 2008. Macrophage differentiation and function in health and disease.. Pathol Int 58(3):143-55 PMID: 18251777
- 5. Schroeder T et al.. 2000. Notch signalling via RBP-J promotes myeloid differentiation.. EMBO J 19(11):2558-68 PMID: 10835354
- 6. Ma AC et al.. 2007. The role of phospholipase C gamma 1 in primitive hematopoiesis during zebrafish development.. Exp Hematol 35(3):368-73 PMID: 17309817
- 7. English D et al.. 1999. Induction of endothelial cell chemotaxis by sphingosine 1-phosphate and stabilization of endothelial monolayer barrier function by lysophosphatidic acid, potential mediators of hematopoietic angiogenesis.. J Hematother Stem Cell Res 8(6):627-34 PMID: 10645770
- 8. Mandal L et al.. 2004. Evidence for a fruit fly hemangioblast and similarities between lymph-gland hematopoiesis in fruit fly and mammal aorta-gonadal-mesonephros mesoderm.. Nat Genet 36(9):1019-23 PMID: 15286786
