Ephrin-B2 reverse signaling is required for axon pathfinding and cardiac valve formation but not early vascular development - PubMed (original) (raw)
Comparative Study
. 2004 Jul 15;271(2):263-71.
doi: 10.1016/j.ydbio.2004.03.026.
Affiliations
- PMID: 15223333
- DOI: 10.1016/j.ydbio.2004.03.026
Free article
Comparative Study
Ephrin-B2 reverse signaling is required for axon pathfinding and cardiac valve formation but not early vascular development
Chad A Cowan et al. Dev Biol. 2004.
Free article
Abstract
Vascular development begins with the formation of a primary vascular plexus that is rapidly remodeled by angiogenesis into the interconnected branched patterns characteristic of mature vasculature. Several receptor tyrosine kinases and their ligands have been implicated to control early development of the vascular system. These include the vascular endothelial growth factor receptors (VEGFR-1 and VEGFR-2) that bind VEGF, the Tie-1 and Tie-2 receptors that bind the angiopoietins, and the EphB4 receptor that binds the membrane-anchored ligand ephrin-B2. Targeted mutations in the mouse germline have revealed essential functions for these molecules in vascular development. In particular, protein-null mutations that delete either EphB4 or ephrin-B2 from the mouse have been shown to result in early embryonic lethality due to failed angiogenic remodeling. The venous expression of EphB4 and arterial expression of ephrin-B2 has lead to the speculation that the interaction of these two molecules leads to bidirectional signaling into both the receptor-expressing cell and the ligand-expressing cell, and that both forward and reverse signals are required for proper development of blood vessels in the embryo. Indeed, targeted removal of the ephrin-B2 carboxy-terminal cytoplasmic tail by another group was shown to perturb vascular development and result in the same early embryonic lethality as the null mutation, leading the authors to propose that ephrin-B2 reverse signaling directs early angiogenic remodeling of the primary vascular plexus [Cell 104 (2001) 57]. However, we show here that the carboxy-terminal cytoplasmic domain of ephrin-B2, and hence reverse signaling, is not required during early vascular development, but it is necessary for neonatal survival and functions later in cardiovascular development in the maturation of cardiac valve leaflets. We further show that ephrin-B2 reverse signaling is required for the pathfinding of axons that form the posterior tract of the anterior commissure. Our results thus indicate that ephrin-B2 functions in the early embryo as a typical instructive ligand to stimulate EphB4 receptor forward signaling during angiogenic remodeling and that later in embryonic development ephrin-B2 functions as a receptor to transduce reverse signals involved in cardiac valve maturation and axon pathfinding.
Similar articles
- Distinct roles of ephrin-B2 forward and EphB4 reverse signaling in endothelial cells.
Hamada K, Oike Y, Ito Y, Maekawa H, Miyata K, Shimomura T, Suda T. Hamada K, et al. Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):190-7. doi: 10.1161/01.atv.0000055440.89758.c2. Arterioscler Thromb Vasc Biol. 2003. PMID: 12588758 - Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth.
Noren NK, Lu M, Freeman AL, Koolpe M, Pasquale EB. Noren NK, et al. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5583-8. doi: 10.1073/pnas.0401381101. Epub 2004 Apr 5. Proc Natl Acad Sci U S A. 2004. PMID: 15067119 Free PMC article. - Regulation of signaling interactions and receptor endocytosis in growing blood vessels.
Pitulescu ME, Adams RH. Pitulescu ME, et al. Cell Adh Migr. 2014;8(4):366-77. doi: 10.4161/19336918.2014.970010. Cell Adh Migr. 2014. PMID: 25482636 Free PMC article. Review. - Ephrin B2 and EphB4 selectively mark arterial and venous vessels in cerebral arteriovenous malformation.
Bai J, Wang YJ, Liu L, Zhao YL. Bai J, et al. J Int Med Res. 2014 Apr;42(2):405-15. doi: 10.1177/0300060513478091. Epub 2014 Feb 11. J Int Med Res. 2014. PMID: 24517927 - The critical role of the interplays of EphrinB2/EphB4 and VEGF in the induction of angiogenesis.
Du E, Li X, He S, Li X, He S. Du E, et al. Mol Biol Rep. 2020 Jun;47(6):4681-4690. doi: 10.1007/s11033-020-05470-y. Epub 2020 Jun 2. Mol Biol Rep. 2020. PMID: 32488576 Review.
Cited by
- Recent advances of the Ephrin and Eph family in cardiovascular development and pathologies.
Zhu Y, Su SA, Shen J, Ma H, Le J, Xie Y, Xiang M. Zhu Y, et al. iScience. 2024 Jul 19;27(8):110556. doi: 10.1016/j.isci.2024.110556. eCollection 2024 Aug 16. iScience. 2024. PMID: 39188984 Free PMC article. Review. - Localized Prox1 Regulates Aortic Valve Endothelial Cell Diversity and Extracellular Matrix Stratification in Mice.
O'Donnell A, Gonzalez BA, Mukherjee S, Wilson R, Alfieri CM, Swoboda CO, Millay DP, Zorn AM, Yutzey KE. O'Donnell A, et al. Arterioscler Thromb Vasc Biol. 2023 Aug;43(8):1478-1493. doi: 10.1161/ATVBAHA.123.319424. Epub 2023 Jun 29. Arterioscler Thromb Vasc Biol. 2023. PMID: 37381982 Free PMC article. - Fold-back mechanism originating inv-dup-del rearrangements in chromosomes 13 and 15.
Burssed B, Zamariolli M, Favilla BP, Meloni VA, Goloni-Bertollo EM, Bellucco FT, Melaragno MI. Burssed B, et al. Chromosome Res. 2023 Feb 24;31(1):10. doi: 10.1007/s10577-023-09720-0. Chromosome Res. 2023. PMID: 36826604 - New Insight on 2D In Vitro Angiogenesis Models: All That Stretches Is Not a Tube.
Beloglazova I, Zubkova E, Dergilev K, Goltseva Y, Parfyonova Y. Beloglazova I, et al. Cells. 2022 Oct 18;11(20):3278. doi: 10.3390/cells11203278. Cells. 2022. PMID: 36291145 Free PMC article. - Insulin-like growth factor binding protein 7 (IGFBP7), a link between heart failure and senescence.
Bracun V, van Essen B, Voors AA, van Veldhuisen DJ, Dickstein K, Zannad F, Metra M, Anker S, Samani NJ, Ponikowski P, Filippatos G, Cleland JGF, Lang CC, Ng LL, Shi C, de Wit S, Aboumsallem JP, Meijers WC, Klip IT, van der Meer P, de Boer RA. Bracun V, et al. ESC Heart Fail. 2022 Dec;9(6):4167-4176. doi: 10.1002/ehf2.14120. Epub 2022 Sep 11. ESC Heart Fail. 2022. PMID: 36088651 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
Research Materials
Miscellaneous