With the identification of a new player, St. Jude researchers expand story of lymphatic development


Oliver, PhD (background) and Rajanavayanan Srinivasan, PhD

St. Jude investigators have identified another gene that plays an essential role in the developing lymphatic system, a finding that helps unravel the formation of this important vascular network and might eventually lead to new strategies for treating lymphatic disorders or blocking cancer’s spread.

The gene, named Coup-TFII, is a nuclear hormone receptor. A team led by St. Jude researchers showed that Coup-TFII activity is necessary to switch on the Prox1 gene early in development of lymphatic progenitor cells. Previous work from the same St. Jude scientists showed Prox1 is the master regulator charged with formation and maintenance of the lymphatic vascular system.

A better understanding of how Prox1 is regulated and how the lymphatic vasculature develops would provide new strategies for stopping the spread of cancer, since metastatic tumors use the vascular network to spread, explained R. Sathish Srinivasan, PhD. He is first author of the study published recently in Genes & Development and a postdoctoral fellow in the laboratory of Guillermo Oliver, PhD, Genetics and Tumor Cell Biology. Oliver is the study’s senior and corresponding author.

Srinivasan said the work also raises hope of someday treating lymphedema by using stem cells to bypass blocked lymph vessels. Lymphedema is a painful and sometimes disfiguring swelling that occurs when the flow of lymph is disrupted, sometimes as a result of cancer or certain treatments.

The latest findings add new details to previous work from Oliver’s laboratory into the origins and functions of the lymphatic system. The system is a network of organs, ducts and vessels that help maintain the body’s fluid balance and serve as a highway through which everything from immune components to cancer cells and lipids move. Oliver said subtle differences in lymphatic function could affect a variety of systems in the body, including the immune response and inflammatory reaction.

Earlier work from Oliver’s laboratory showed the lymphatic vascular system develops from cells in embryonic veins that give rise to lymphatic endothelial cells or LECs. Prox1 is expressed in the LECs, which are released from the veins during embryonic development and migrate throughout the body.

Although the transcription factor Sox18 is required to trigger Prox1production in LECs, Oliver said investigators suspected Sox18 alone was not enough to switch on Prox1in LEC progenitors. That’s because Sox18 is produced in cells that give rise to both arteries and veins, but Prox1 is only expressed in venous cells.

Working with several strains of mutant mice, Oliver and his colleagues identified Coup-TFII as the other important player required for Prox1expression. Coup-TFII works by binding to a promoter region of the Prox1 gene. Additional studies found that although Coup-TFII is needed to maintain Prox1 production early in development, Prox1 quickly becomes self-regulating.

Without Prox1, the lymphatic vascular system starts to acquire features reminiscent of blood vessels. Oliver said such plasticity might someday prove useful for treating cancer and other disorders.

The study’s other St. Jude authors are Xin Geng, PhD; Ying Yang, PhD; Yingdi Wang, PhD, and Oleg Lagutin, PhD, all of Genetics and Tumor Cell Biology; and Suraj Mukatira, Hartwell Center for Bioinformatics and Biotechnology.

May 2010


Email This Article Email This Article   |   Print Print