Lineage-specific requirement for RNA and DNA unwinding during lymphatic endothelial cell proliferation

Lineage-specific requirement for RNA and DNA unwinding during lymphatic endothelial cell proliferation

Speaker: Dr Kaska Koltowska, Department of Immunology, Genetics and Pathology, Uppsala University

Host:  Claudia Linker

Abstract: Developing tissues undergo timely regulated cell divisions in order to form proportional organs. Cell division requires DNA and RNA synthesis, processes dependent on general cellular machinery. Yet, during development cell proliferation is highly regulated resulting in differently sized tissues. To date little is known about how these general factors guide these processes in a tissue specific manner. Here we uncovered a new role for an RNA helicase and Topoisomerase during lymphatic development.

In a forward genetic screen to identify novel factors required for lymphangiogenesis, the dead-box helicase 21 (ddx21) and topoisomerase 3a (top3a) have been identified, due to a loss of the thoracic duct. Phenotypic analysis of the lymphatic network using lymphatic transgenic marker strains, revealed decreased numbers of lymphatic progenitors. The lymphatic phenotypes resulted from underlying defects in cell cycle progression of endothelial cells. As vegfc/vegfr3 are the key growth factors regulating lymphatic endothelial cell proliferation, we examined if ddx21 or top3a act in vegfc/vegfr3 dependent manner. We found that upon ectopic overexpression of Vegfc, the cell proliferation is indeed dependent on ddx21 or top3a identifying them as necessary downstream components of this signalling pathway.

These mutants offer unique insights into how an expansion of a new vasculature from a limited pool of progenitors is regulated. This study will further expand our knowledge how general factors involved in basic cell machinery act in tissue specific manner.