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Open Access Highly Accessed Research article

Embryonic vascular endothelial cells are malleable to reprogramming via Prox1 to a lymphatic gene signature

Harold Kim1, Vicky PKH Nguyen1, Tatiana V Petrova23, Maribelle Cruz1, Kari Alitalo2 and Daniel J Dumont1*

Author Affiliations

1 Sunnybrook Research Institute University of Toronto 2075 Bayview Avenue Toronto, Ontario, M4N 3M5, Canada

2 Biomedicum Helsinki Haartman Institute PO Box 63 (Haartmaninkatu 8) FI-00014 University of Helsinki, Helsinki, Finland

3 Division of Experimental Oncology CePO, CHUV and University of Lausanne 155, Chemin des Boveresses CH-1066 Epalinges Switzerland

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BMC Developmental Biology 2010, 10:72  doi:10.1186/1471-213X-10-72

Published: 28 June 2010

Abstract

Background

In vivo studies demonstrate that the Prox1 transcription factor plays a critical role in the development of the early lymphatic system. Upon Prox1 expression, early lymphatic endothelial cells differentiate from the cardinal vein and begin to express lymphatic markers such as VEGFR-3, LYVE-1 and Podoplanin. Subsequent in vitro studies have found that differentiated vascular endothelial cells can be reprogrammed by Prox1 to express a lymphatic gene profile, suggesting that Prox1 can initiate the expression of a unique gene signature during lymphangiogenesis. While the in vitro data suggest that gene reprogramming occurs upon Prox1 expression, it is not clear if this is a direct result of Prox1 in vascular endothelial cells in vivo.

Results

Overexpression of Prox1 in vascular endothelial cells during embryonic development results in the reprogramming of genes to that of a more lymphatic signature. Consequent to this overexpression, embryos suffer from gross edema that results in embryonic lethality at E13.5. Furthermore, hemorrhaging and anemia is apparent along with clear defects in lymph sac development. Alterations in junctional proteins resulting in an increase in vascular permeability upon Prox1 overexpression may contribute to the complications found during embryonic development.

Conclusion

We present a novel mouse model that addresses the importance of Prox1 in early embryonic lymphangiogenesis. It is clear that there needs to be a measured pattern of expression of Prox1 during embryonic development. Furthermore, Prox1 reprograms vascular endothelial cells in vivo by creating a molecular signature to that of a lymphatic endothelial cell.