Abnormal angiogenesis but intact hematopoietic potential in TGF-ß type I receptor-deficient mice

Jonas Larsson, Marie-José Goumans¹, Lottie Jansson Sjöstrand, Marga A. van Rooijen², Dorien Ward², Per Levéen, Xiufeng Xu, Peter ten Dijke¹, Christine L. Mummery², and Stefan Karlsson³

Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine and Department of Medicine, Lund University Hospital, Lund, Sweden, ¹Netherlands Cancer Institute, Amsterdam and ²Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht, The Netherlands ³Corresponding author e-mail: Stefan.Karlsson{at}molmed.lu.se

Abstract: Deletion of the transforming growth factor ß1 (TGF-ß1) gene in mice has previously suggested that it regulates both hematopoiesis and angiogenesis. To define the function of TGF-ß more precisely, we inactivated the TGF-ß type I receptor (TßRI) gene by gene targeting. Mice lacking TßRI die at midgestation, exhibiting severe defects in vascular development of the yolk sac and placenta, and an absence of circulating red blood cells. However, despite obvious anemia in the TßRI^–/– yolk sacs, clonogenic assays on yolk sac-derived hematopoietic precursors in vitro revealed that TßRI^–/– mice exhibit normal hematopoietic potential compared with wild-type and heterozygous siblings. Endothelial cells derived from TßRI-deficient embryos show enhanced cell proliferation, improper migratory behavior and impaired fibronectin production in vitro, defects that are associated with the vascular defects seen in vivo. We thus demonstrate here that, while TßRI is crucial for the function of TGF-ß during vascular development and can not be compensated for by the activin receptor-like kinase-1 (ALK-1), functional hematopoiesis and development of hematopoietic progenitors is not dependent on TGF-ß signaling via TßRI.

Key Words: Keywords: endothelial cell/hematopoiesis/serine/signal transduction/TGF-ß/threonine kinase receptor