Med the experiments: LB. Analyzed the data: LB. Contributed reagents/materials/analysis tools: JEM. Wrote the paper: LB JEM.
Subsequent to vasculogenesis, endothelial cells specialize into arterial and venous cell types through a complex mechanism that 22948146 starts with a number of key signaling molecules. The Notch receptor system is one of the pathways that have been implicated to play a critical role in the determination of arterial cell fate [1?]. Perturbation of the Notch receptor or its ligand Dll4 inhibits the development of an arterial cell fate from the venous endothelium, characterized by the downregulation of artery-specific markers such as EphrinB2 and Notch5. Conversely, venous markers are upregulated such as EphB4 [1]. Similar to arteries, the fate of the venous endothelium also appears to have a determined molecular program. Specifically, the transcription factor COUP-TFII has been found to repress the arterial phenotype; deletion of COUPTFII results in the upregulation of NP-1 and Notch resulting in the arterialization of venous endothelium [4]. With the establishment of the venous system, the formation of the lymphatic vasculature was found to originate from the cardinal vein [5?]. The Prox1 transcription factor has been identified to be necessary and sufficient in initiating the early differentiation of the lymphatic system, its polarized expression starting at E9.75 [8,9]. These Prox1 expressing endothelial cells then bud from the cardinal vein and migrate to form the early lymph sac [10,11]. Lymph sac expansion appears to be under the influence of guidance cues driven by the VEGF-C ligand; loss of this growth factor results in the inability of early lymphatic endothelial cells to migrate from the cardinal vein into the interstitium resulting in no lymph sac formation, edema and embryonic lethality [12]. In vitro, the ectopic expression of Prox1 in blood endothelial cells has been found to correlate with their reprogramming to a more lymphaticlike gene TA02 site profile [13,14]. Furthermore, we have observed that vascular specific overexpression of Prox1 in the developing embryo also results in the reprogramming of the vasculature to a more lymphatic signature [15]. A number of early fate decisions are made at the molecular and cellular level during embryonic lymphangiogenesis. One interesting and confounding aspect of the early patterning of Prox1 is its specific and polarized expression on the cardinal vein [10,11]. One potential mechanism driving 15755315 this pattern involves the transcription factor Sox18, which has been found to regulate Prox1 on early venous endothelial cells. Loss of Sox18 leads to a loss of Prox1 expression, an inability to form lymph sac structures, edema, and embryonic lethality [16]. Given this, it is still not completely clear how lymphatic polarization is regulated or how Prox1 and Sox18 are found specifically on the venous endothelium and not on the closely related and juxtaposed dorsal aorta. One can speculate that like the specific expression pattern of Sox18, the segregation of other molecular Anlotinib signatures may influence lymphatic specificity [17,18]. In this report we further characterize a transgenic model that forces Prox1 expression in vascular endothelial cells. The ability of Prox1 to reprogram blood endothelial cells is apparent in our in vivo model [15], solidifying the importance of Prox1 in changing the venous gene signature to that of a more lymphatic profile. Significantly, we also find that during e.Med the experiments: LB. Analyzed the data: LB. Contributed reagents/materials/analysis tools: JEM. Wrote the paper: LB JEM.
Subsequent to vasculogenesis, endothelial cells specialize into arterial and venous cell types through a complex mechanism that 22948146 starts with a number of key signaling molecules. The Notch receptor system is one of the pathways that have been implicated to play a critical role in the determination of arterial cell fate [1?]. Perturbation of the Notch receptor or its ligand Dll4 inhibits the development of an arterial cell fate from the venous endothelium, characterized by the downregulation of artery-specific markers such as EphrinB2 and Notch5. Conversely, venous markers are upregulated such as EphB4 [1]. Similar to arteries, the fate of the venous endothelium also appears to have a determined molecular program. Specifically, the transcription factor COUP-TFII has been found to repress the arterial phenotype; deletion of COUPTFII results in the upregulation of NP-1 and Notch resulting in the arterialization of venous endothelium [4]. With the establishment of the venous system, the formation of the lymphatic vasculature was found to originate from the cardinal vein [5?]. The Prox1 transcription factor has been identified to be necessary and sufficient in initiating the early differentiation of the lymphatic system, its polarized expression starting at E9.75 [8,9]. These Prox1 expressing endothelial cells then bud from the cardinal vein and migrate to form the early lymph sac [10,11]. Lymph sac expansion appears to be under the influence of guidance cues driven by the VEGF-C ligand; loss of this growth factor results in the inability of early lymphatic endothelial cells to migrate from the cardinal vein into the interstitium resulting in no lymph sac formation, edema and embryonic lethality [12]. In vitro, the ectopic expression of Prox1 in blood endothelial cells has been found to correlate with their reprogramming to a more lymphaticlike gene profile [13,14]. Furthermore, we have observed that vascular specific overexpression of Prox1 in the developing embryo also results in the reprogramming of the vasculature to a more lymphatic signature [15]. A number of early fate decisions are made at the molecular and cellular level during embryonic lymphangiogenesis. One interesting and confounding aspect of the early patterning of Prox1 is its specific and polarized expression on the cardinal vein [10,11]. One potential mechanism driving 15755315 this pattern involves the transcription factor Sox18, which has been found to regulate Prox1 on early venous endothelial cells. Loss of Sox18 leads to a loss of Prox1 expression, an inability to form lymph sac structures, edema, and embryonic lethality [16]. Given this, it is still not completely clear how lymphatic polarization is regulated or how Prox1 and Sox18 are found specifically on the venous endothelium and not on the closely related and juxtaposed dorsal aorta. One can speculate that like the specific expression pattern of Sox18, the segregation of other molecular signatures may influence lymphatic specificity [17,18]. In this report we further characterize a transgenic model that forces Prox1 expression in vascular endothelial cells. The ability of Prox1 to reprogram blood endothelial cells is apparent in our in vivo model [15], solidifying the importance of Prox1 in changing the venous gene signature to that of a more lymphatic profile. Significantly, we also find that during e.
