Development, Vol 118, Issue 2 489-498, Copyright © 1993 by Company of Biologists

JOURNAL ARTICLES

flk-1, an flt-related receptor tyrosine kinase is an early marker for endothelial cell precursors

TP Yamaguchi, DJ Dumont, RA Conlon, ML Breitman and J Rossant
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

We have used RT-PCR to screen pluripotent murine embryonic stem cells to identify receptor tyrosine kinases (RTKs) potentially involved in the determination or differentiation of cell lineages during early mouse development. Fourteen different tyrosine kinase sequences were identified. The expression patterns of four RTKs have been examined and all are expressed in the mouse embryo during, or shortly after, gastrulation. We report here the detailed expression pattern of one such RTK, the flt-related gene flk-1. In situ hybridization analysis of the late primitive streak stage embryo revealed that flk-1 was expressed in the proximal-lateral embryonic mesoderm; tissue fated to become heart. By headfold stages, staining was confined to the endocardial cells of the heart primordia as well as to the blood islands of the visceral yolk sac and the developing allantois. Patchy, speckled staining was detected in the endothelium of all the major embryonic and extraembryonic blood vessels as they formed. During early organogenesis, expression was detected in the blood vessels of highly vascularized tissues such as the brain, liver, lungs and placenta. Since flk-1 was expressed in early mesodermal cells prior to any morphological evidence for endothelial cell differentiation (vasculogenesis), as well as in cells that form blood vessels from preexisting ones (angiogenesis), it appears to be a very early marker of endothelial cell precursors. We have previously reported that another novel RTK, designated tek, was expressed in differentiating endothelial cells. We show here that flk-1 transcripts are expressed one full embryonic day earlier than the first tek transcripts. The expression of these two RTKs appear to correlate with the specification and early differentiation of the endothelial cell lineage respectively, and therefore may play important roles in the establishment of this lineage.
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				A. Kappel, V. Ronicke, A. Damert, I. Flamme, W. Risau, and G. Breier Identification of Vascular Endothelial Growth Factor (VEGF) Receptor-2 (Flk-1) Promoter/Enhancer Sequences Sufficient for Angioblast and Endothelial Cell-Specific Transcription in Transgenic Mice Blood, June 15, 1999; 93(12): 4284 - 4292. [Abstract] [Full Text] [PDF]

				F. A. Pereira, Y. Qiu, G. Zhou, M.-J. Tsai, and S. Y. Tsai The orphan nuclear receptor COUP-TFII is required for angiogenesis and heart development Genes & Dev., April 15, 1999; 13(8): 1037 - 1049. [Abstract] [Full Text]

				A. C. Schuh, P. Faloon, Q.-L. Hu, M. Bhimani, and K. Choi In vitro hematopoietic and endothelial potential of flk-1-/- embryonic stem cells and embryos PNAS, March 2, 1999; 96(5): 2159 - 2164. [Abstract] [Full Text] [PDF]

				M. Ogawa, M. Kizumoto, S. Nishikawa, T. Fujimoto, H. Kodama, and S.-I. Nishikawa Expression of alpha 4-Integrin Defines the Earliest Precursor of Hematopoietic Cell Lineage Diverged From Endothelial Cells Blood, February 15, 1999; 93(4): 1168 - 1177. [Abstract] [Full Text] [PDF]

				M. Hirashima, H. Kataoka, S. Nishikawa, N. Matsuyoshi, and S.-I. Nishikawa Maturation of Embryonic Stem Cells Into Endothelial Cells in an In Vitro Model of Vasculogenesis Blood, February 15, 1999; 93(4): 1253 - 1263. [Abstract] [Full Text] [PDF]

				Y. Wu and C. Patterson The Human KDR/flk-1 Gene Contains a Functional Initiator Element That Is Bound and Transactivated by TFII-I J. Biol. Chem., January 29, 1999; 274(5): 3207 - 3214. [Abstract] [Full Text] [PDF]

				S. Kinder, T. Tsang, G. Quinlan, A. Hadjantonakis, A Nagy, and P. Tam The orderly allocation of mesodermal cells to the extraembryonic structures and the anteroposterior axis during gastrulation of the mouse embryo Development, January 11, 1999; 126(21): 4691 - 4701. [Abstract] [PDF]

				J Palis, S Robertson, M Kennedy, C Wall, and G Keller Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse Development, January 11, 1999; 126(22): 5073 - 5084. [Abstract] [PDF]

				A Perea-Gomez, W Shawlot, H Sasaki, R. Behringer, and S Ang HNF3beta and Lim1 interact in the visceral endoderm to regulate primitive streak formation and anterior-posterior polarity in the mouse embryo Development, January 10, 1999; 126(20): 4499 - 4511. [Abstract] [PDF]

				Y Saga, S Miyagawa-Tomita, A Takagi, S Kitajima, J. Miyazaki, and T Inoue MesP1 is expressed in the heart precursor cells and required for the formation of a single heart tube Development, January 8, 1999; 126(15): 3437 - 3447. [Abstract] [PDF]

				G. Fong, L Zhang, D. Bryce, and J Peng Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice Development, January 7, 1999; 126(13): 3015 - 3025. [Abstract] [PDF]

				H Nishina, C Vaz, P Billia, M Nghiem, T Sasaki, J. De la Pompa, K Furlonger, C Paige, C Hui, K. Fischer, et al. Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4 Development, January 2, 1999; 126(3): 505 - 516. [Abstract] [PDF]

				T. Korff and H. G. Augustin Integration of Endothelial Cells in Multicellular Spheroids Prevents Apoptosis and Induces Differentiation J. Cell Biol., November 30, 1998; 143(5): 1341 - 1352. [Abstract] [Full Text] [PDF]

				W. G. Roberts, J. Delaat, M. Nagane, S. Huang, W. K. Cavenee, and G. E. Palade Host Microvasculature Influence on Tumor Vascular Morphology and Endothelial Gene Expression Am. J. Pathol., October 1, 1998; 153(4): 1239 - 1248. [Abstract] [Full Text] [PDF]

				B. Robert, P. L. St. John, and D. R. Abrahamson Direct visualization of renal vascular morphogenesis in Flk1 heterozygous mutant mice Am J Physiol Renal Physiol, July 1, 1998; 275(1): F164 - F172. [Abstract] [Full Text] [PDF]

				E. C. Liao, B. H. Paw, A. C. Oates, S. J. Pratt, J. H. Postlethwait, and L. I. Zon SCL/Tal-1 transcription factor acts downstream of cloche to specify hematopoietic and vascular progenitors in zebrafish Genes & Dev., March 1, 1998; 12(5): 621 - 626. [Abstract] [Full Text]