Vascular endothelial cell lineage-specific promoter in transgenic mice

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Vascular endothelial cell lineage-specific promoter in transgenic mice

TM Schlaeger, Y Qin, Y Fujiwara, J Magram and TN Sato
Roche Institute of Molecular Biology, Roche Research Center, Nutley, New Jersey 07110-1199, USA.

Vascular endothelial cells play essential roles in the function and development of the cardiovascular system. However, due to the lack of lineage-specific markers suitable for molecular and biochemical analyses, very little is known about the molecular mechanisms that regulate endothelial cell differentiation. We report the first vascular endothelial cell lineage-specific (including angioblastic precursor cells) 1.2 kb promoter in transgenic mice. Moreover, deletion analysis of this promoter region in transgenic embryos revealed multiple elements that are required for the maximum endothelial cell lineage-specific expression. This is a powerful molecular tool that will enable us to identify factors and cellular signals essential for the establishment of vascular endothelial cell lineage. It will also allow us to deliver genes specifically into this cell type in vivo to test specifically molecules that have been implicated in cardiovascular development. Furthermore, we have established embryonic stem (ES) cells from the blastocysts of the transgenic mouse that carry the 1.2 kb promoter-LacZ reporter transgene. These ES cells were able to differentiate in vitro to form cystic embryoid bodies (CEB) that contain endothelial cells determined by PECAM immunohistochemistry. However, these in vitro differentiated endothelial cells did not express the LacZ reporter gene. This indicates the lack of factors and/or cellular interactions which are required to induce the expression of the reporter gene mediated by this 1.2 kb promoter in this in vitro differentiation system. Thus this system will allow us to screen for the putative inducers that exist in vivo but not in vitro. These putative inducers are presumably important for in vivo differentiation of vascular endothelial cells.

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				T. V. Cohen, O. Kosti, and C. L. Stewart The nuclear envelope protein MAN1 regulates TGF{beta} signaling and vasculogenesis in the embryonic yolk sac Development, April 1, 2007; 134(7): 1385 - 1395. [Abstract] [Full Text] [PDF]

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				L. R. Mollica, J. T. B. Crawley, K. Liu, J. B. Rance, P. N. Cockerill, G. A. Follows, J.-R. Landry, D. J. Wells, and D. A. Lane Role of a 5'-enhancer in the transcriptional regulation of the human endothelial cell protein C receptor gene Blood, August 15, 2006; 108(4): 1251 - 1259. [Abstract] [Full Text] [PDF]

				K. E. Inman and K. M. Downs Brachyury is required for elongation and vasculogenesis in the murine allantois Development, August 1, 2006; 133(15): 2947 - 2959. [Abstract] [Full Text] [PDF]

				D. C. Goldman, R. Hackenmiller, T. Nakayama, S. Sopory, C. Wong, H. Kulessa, and J. L. Christian Mutation of an upstream cleavage site in the BMP4 prodomain leads to tissue-specific loss of activity Development, May 15, 2006; 133(10): 1933 - 1942. [Abstract] [Full Text] [PDF]

				K. E. Fathers, C. M. Stone, K. Minhas, J. J.A. Marriott, J. D. Greenwood, D. J. Dumont, and B. L. Coomber Heterogeneity of Tie2 Expression in Tumor Microcirculation: Influence of Cancer Type, Implantation Site, and Response to Therapy Am. J. Pathol., December 1, 2005; 167(6): 1753 - 1762. [Abstract] [Full Text] [PDF]

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				K. M. Ruppel, D. Willison, H. Kataoka, A. Wang, Y.-W. Zheng, I. Cornelissen, L. Yin, S. M. Xu, and S. R. Coughlin Essential role for G{alpha}13 in endothelial cells during embryonic development PNAS, June 7, 2005; 102(23): 8281 - 8286. [Abstract] [Full Text] [PDF]

				J. T. B. Crawley, J. K. Lam, J. B. Rance, L. R. Mollica, J. S. O'Donnell, and D. A. Lane Proteolytic inactivation of ADAMTS13 by thrombin and plasmin Blood, February 1, 2005; 105(3): 1085 - 1093. [Abstract] [Full Text] [PDF]

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				X. Chu, J. Chen, M. C. Reedy, C. Vera, K.-L. P. Sung, and L. A. Sung E-Tmod capping of actin filaments at the slow-growing end is required to establish mouse embryonic circulation Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1827 - H1838. [Abstract] [Full Text] [PDF]

				S. S. Gerety and D. J. Anderson Cardiovascular ephrinB2 function is essential for embryonic angiogenesis Development, March 5, 2003; 129(6): 1397 - 1410. [Abstract] [Full Text] [PDF]

				T. Takahashi, K. Takahashi, P. L. St. John, P. A. Fleming, T. Tomemori, T. Watanabe, D. R. Abrahamson, C. J. Drake, T. Shirasawa, and T. O. Daniel A Mutant Receptor Tyrosine Phosphatase, CD148, Causes Defects in Vascular Development Mol. Cell. Biol., March 1, 2003; 23(5): 1817 - 1831. [Abstract] [Full Text] [PDF]

				T. Minami, D. J. Donovan, J. C. Tsai, R. D. Rosenberg, and W. C. Aird Differential regulation of the von Willebrand factor and Flt-1 promoters in the endothelium of hypoxanthine phosphoribosyltransferase-targeted mice Blood, December 1, 2002; 100(12): 4019 - 4025. [Abstract] [Full Text] [PDF]

				J. L. Vivian, Y. Chen, D. Yee, E. Schneider, and T. Magnuson An allelic series of mutations in Smad2 and Smad4 identified in a genotype-based screen of N-ethyl-N- nitrosourea-mutagenized mouse embryonic stem cells PNAS, November 26, 2002; 99(24): 15542 - 15547. [Abstract] [Full Text] [PDF]

				P. I. Teng, M. R. Dichiara, L. G. Komuves, K. Abe, T. Quertermous, and J. N. Topper Inducible and selective transgene expression in murine vascular endothelium Physiol Genomics, October 29, 2002; 11(2): 99 - 107. [Abstract] [Full Text] [PDF]

				R. P. Visconti, C. D. Richardson, and T. N. Sato Orchestration of angiogenesis and arteriovenous contribution by angiopoietins and vascular endothelial growth factor (VEGF) PNAS, June 11, 2002; 99(12): 8219 - 8224. [Abstract] [Full Text] [PDF]

				Y. Peng and N. Jahroudi The NFY transcription factor functions as a repressor and activator of the von Willebrand factor promoter Blood, April 1, 2002; 99(7): 2408 - 2417. [Abstract] [Full Text] [PDF]

				M.-J. Sanchez, E.-O. Bockamp, J. Miller, L. Gambardella, and A. R. Green Selective rescue of early haematopoietic progenitors in Scl-/- mice by expressing Scl under the control of a stem cell enhancer Development, December 1, 2001; 128(23): 4815 - 4827. [Abstract] [Full Text] [PDF]

				A. Willuweit, G. Sass, A. Schoneberg, U. Eisel, G. Tiegs, and M. Clauss Chronic Inflammation and Protection from Acute Hepatitis in Transgenic Mice Expressing TNF in Endothelial Cells J. Immunol., October 1, 2001; 167(7): 3944 - 3952. [Abstract] [Full Text] [PDF]

				C. T. Griffin, Y. Srinivasan, Y.-W. Zheng, W. Huang, and S. R. Coughlin A Role for Thrombin Receptor Signaling in Endothelial Cells During Embryonic Development Science, August 31, 2001; 293(5535): 1666 - 1670. [Abstract] [Full Text] [PDF]