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Gene targeting of tissue factor, factor X, and factor VII in mice: their involvement in embryonic development
1Biotechnology Center of Oslo, P.O.B. 1125 Blindern, N-0317 Oslo, Norway.
Abstract:
Inactivation of specific genes in mammals by gene targeting has accelerated our ability to determine gene function. Nearly all genes involved in the blood coagulation system have been knocked out in mice. Tissue factor (TF) is the main initiator of the coagulation system and functions as a cell surface receptor for coagulation factor VII (FVII). Knockout studies have shown that TF deficiency results in lethality around embryonic day (E) 8.5-10.5. The results suggest a role for TF in embryonic blood vessel development and maintenance of vascular integrity in the yolk sac. In addition, TF may be involved in the maintenance of the placental labyrinth. Factor X (FX) deficiency causes partial embryonic lethality between E11.5-12.5. FX-/- mice that were born died from fatal neonatal bleeding. In contrast, FVII deficiency is not embryonic lethal, but FVII-/- neonates died from hemorrhage within the first days after birth. The various lethal phenotypes of deficiencies of the different coagulation factors suggest involvement in processes beyond hemostasis. Both TF/FVIIa and FXa can trigger intracellular signaling events in certain cell types. Signaling by coagulation proteases and protease-activated receptors (PARs) may have important roles in embryonic development.
Insights
Gene targeting in mice reveals critical roles for blood coagulation factors beyond hemostasis. Tissue factor deficiency causes embryonic lethality, suggesting its importance in vascular development and placental integrity.
Area of Science:
- Biochemistry
- Developmental Biology
- Genetics
Background:
- Gene targeting in mammals is crucial for understanding gene function.
- Most blood coagulation genes have been studied via knockout mice.
- Tissue factor (TF) initiates coagulation and binds factor VII (FVII).
Purpose of the Study:
- To investigate the function of coagulation factors in embryonic development.
- To explore roles of TF, FVII, and FX beyond hemostasis.
Main Methods:
- Gene targeting to create knockout mice for coagulation factors.
- Analysis of embryonic lethality and neonatal phenotypes in knockout models.
Main Results:
- TF deficiency leads to embryonic lethality around E8.5-10.5, indicating roles in vascular development and integrity.
- FX deficiency causes partial embryonic lethality and neonatal bleeding.
- FVII deficiency results in neonatal hemorrhage but is not embryonic lethal.
- Coagulation proteases like TF/FVIIa and FXa can trigger intracellular signaling.
Conclusions:
- Coagulation factors play vital roles in embryonic development beyond blood clotting.
- TF is essential for embryonic vascular integrity and placental development.
- Signaling pathways involving coagulation proteases and PARs may be critical during embryogenesis.