DOI QR코드

DOI QR Code

Alk3/Alk3b and Smad5 Mediate BMP Signaling during Lymphatic Development in Zebrafish

  • Kim, Jun-Dae (Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine) ;
  • Kim, Jongmin (Department of Life Systems, Sookmyung Women's University)
  • Received : 2014.01.09
  • Accepted : 2014.03.06
  • Published : 2014.03.31

Abstract

Lymphatic vessels are essential to regulate interstitial fluid homeostasis and diverse immune responses. A number of crucial factors, such as VEGFC, SOX18, PROX1, FOX2C, and GJC2, have been implicated in differentiation and/or maintenance of lymphatic endothelial cells (LECs). In humans, dysregulation of these genes is known to cause lymphedema, a debilitating condition which adversely impacts the quality of life of affected individuals. However, there are no currently available pharmacological treatments for lymphedema, necessitating identification of additional factors modulating lymphatic development and function which can be targeted for therapy. In this report, we investigate the function of genes associated with Bone Morphogenetic Protein (BMP) signaling in lymphatic development using zebrafish embryos. The knock-down of BMP type II receptors, Bmpr2a and Bmpr2b, and type I receptors, Alk3 and Alk3b, as well as SMAD5, an essential cellular mediator of BMP signaling, led to distinct lymphatic defects in developing zebrafish. Therefore, it appears that each constituent of the BMP signaling pathway may have a unique function during lymphatic development. Taken together, our data demonstrate that BMP signaling is essential for normal lymphatic vessel development in zebrafish.

Keywords

References

  1. Abdelwahid, E., Rice, D., Pelliniemi, L.J., and Jokinen, E. (2001). Overlapping and differential localization of Bmp-2, Bmp-4, Msx-2 and apoptosis in the endocardial cushion and adjacent tissues of the developing mouse heart. Cell Tissue Res. 305, 67-78. https://doi.org/10.1007/s004410100399
  2. Bauer, H., Lele, Z., Rauch, G.J., Geisler, R., and Hammerschmidt, M. (2001). The type I serine/threonine kinase receptor Alk8/Losta-fin is required for Bmp2b/7 signal transduction during dorsoventral patterning of the zebrafish embryo. Development 128, 849-858.
  3. Beets, K., Huylebroeck, D., Moya, I.M., Umans, L., and Zwijsen, A. (2013). Robustness in angiogenesis: notch and BMP shaping waves. Trends Genet. 29, 140-149. https://doi.org/10.1016/j.tig.2012.11.008
  4. Chocron, S., Verhoeven, M.C., Rentzsch, F., Hammerschmidt, M., and Bakkers, J. (2007). Zebrafish Bmp4 regulates left-right asymmetry at two distinct developmental time points. Dev. Biol. 305, 577-588. https://doi.org/10.1016/j.ydbio.2007.03.001
  5. Collery, R.F., and Link, B.A. (2011). Dynamic smad-mediated BMP signaling revealed through transgenic zebrafish. Dev. Dyn. 240, 712-722. https://doi.org/10.1002/dvdy.22567
  6. David, L., Feige, J.J., and Bailly, S. (2009). Emerging role of bone morphogenetic proteins in angiogenesis. Cytokine Growth Factor Rev. 20, 203-212. https://doi.org/10.1016/j.cytogfr.2009.05.001
  7. Dick, A., Meier, A., and Hammerschmidt, M. (1999). Smad1 and Smad5 have distinct roles during dorsoventral patterning of the zebrafish embryo. Dev. Dyn. 216, 285-298. https://doi.org/10.1002/(SICI)1097-0177(199911)216:3<285::AID-DVDY7>3.0.CO;2-L
  8. Dunworth, W.P., Cardona-Costa, J., Cagavi, E., Kim, J.D., Fischer, J.C., Meadows, S., Wang, Y., Cleaver, O., Qyang, Y., Ober, E. A., et al. (2013). Bone morphogenetic protein 2 signaling negatively modulates lymphatic development in vertebrate embryos. Circ. Res. 114, 56-66.
  9. Ehrlich, M., Horbelt, D., Marom, B., Knaus, P., and Henis, Y.I. (2011). Homomeric and heteromeric complexes among TGF-$\beta$ and BMP receptors and their roles in signaling. Cell Signal. 23, 1424-1432. https://doi.org/10.1016/j.cellsig.2011.04.004
  10. Eisenberg, L.M., and Markwald, R.R. (1995). Molecular regulation of atrioventricular valvuloseptal morphogenesis. Circ. Res. 77, 1-6. https://doi.org/10.1161/01.RES.77.1.1
  11. Farnsworth, R.H., Karnezis, T., Shayan, R., Matsumoto, M., Nowell, C.J., Achen, M.G., and Stacker, S.A. (2011). A role for bone morphogenetic protein-4 in lymph node vascular remodeling and primary tumor growth. Cancer Res. 71, 6547-6557. https://doi.org/10.1158/0008-5472.CAN-11-0200
  12. Finkenzeller, G., Hager, S., and Stark, G.B. (2012). Effects of bone morphogenetic protein 2 on human umbilical vein endothelial cells. Microvasc. Res. 84, 81-85. https://doi.org/10.1016/j.mvr.2012.03.010
  13. Guo, J., and Wu, G. (2012). The signaling and functions of heterodimeric bone morphogenetic proteins. Cytokine Growth Factor Rev. 23, 61-67. https://doi.org/10.1016/j.cytogfr.2012.02.001
  14. Hartung, A., Bitton-Worms, K., Rechtman, M.M., Wenzel, V., Boergermann, J.H., Hassel, S., Henis, Y.I., and Knaus, P. (2006). Different routes of bone morphogenic protein (BMP) receptor endocytosis influence BMP signaling. Mol. Cell. Biol. 26, 7791-7805. https://doi.org/10.1128/MCB.00022-06
  15. Kawabata, M., Imamura, T., and Miyazono, K. (1998). Signal transduction by bone morphogenetic proteins. Cytokine Growth Factor Rev. 9, 49-61. https://doi.org/10.1016/S1359-6101(97)00036-1
  16. Kim, J.D., Kang, H., Larrivee, B., Lee, M.Y., Mettlen, M., Schmid, S.L., Roman, B.L., Qyang, Y., Eichmann, A., and Jin, S.W. (2012). Context-dependent proangiogenic function of bone morphogenetic protein signaling is mediated by disabled homolog 2. Dev. Cell 23, 441-448. https://doi.org/10.1016/j.devcel.2012.07.007
  17. Kim, J.D., Kang, Y., Kim, J., Papangeli, I., Kang, H., Wu, J., Park, H., Nadelmann, E., Rockson, S.G., Chun, H.J., et al. (2013). Essential role of apelin signaling during lymphatic development in Zebrafish. Arterioscler. Thromb. Vasc. Biol. 34, 338-345.
  18. Kinashi, H., Ito, Y., Mizuno, M., Suzuki, Y., Terabayashi, T., Nagura, F., Hattori, R., Matsukawa, Y., Mizuno, T., Noda, Y., et al. (2013). TGF-$\beta1$ promotes lymphangiogenesis during peritoneal fibrosis. J. Am. Soc. Nephrol. 24, 1627-1642. https://doi.org/10.1681/ASN.2012030226
  19. Kondo, M. (2007). Bone morphogenetic proteins in the early development of zebrafish. FEBS J. 274, 2960-2967. https://doi.org/10.1111/j.1742-4658.2007.05838.x
  20. Larrivee, B., Prahst, C., Gordon, E., del Toro, R., Mathivet, T., Duarte, A., Simons, M., and Eichmann, A. (2012). ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway. Dev. Cell 22, 489-500. https://doi.org/10.1016/j.devcel.2012.02.005
  21. Levet, S., Ciais, D., Merdzhanova, G., Mallet, C., Zimmers, T.A., Lee, S.J., Navarro, F.P., Texier, I., Feige, J.J., Bailly, S., et al. (2013). Bone morphogenetic protein 9 (BMP9) controls lymphatic vessel maturation and valve formation. Blood 122, 598-607. https://doi.org/10.1182/blood-2012-12-472142
  22. Little, S.C., and Mullins, M.C. (2009). Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes to pattern the dorsoventral axis. Nat. Cell Biol. 11, 637-643. https://doi.org/10.1038/ncb1870
  23. McReynolds, L.J., Gupta, S., Figueroa, M.E., Mullins, M.C., and Evans, T. (2007). Smad1 and Smad5 differentially regulate embryonic hematopoiesis. Blood 110, 3881-3890. https://doi.org/10.1182/blood-2007-04-085753
  24. Miyazono, K., Kamiya, Y., and Morikawa, M. (2010). Bone morphogenetic protein receptors and signal transduction. J. Biochem. 147, 35-51. https://doi.org/10.1093/jb/mvp148
  25. Moya, I.M., Umans, L., Maas, E., Pereira, P.N., Beets, K., Francis, A., Sents, W., Robertson, E.J., Mummery, C.L., Huylebroeck, D., et al. (2012). Stalk cell phenotype depends on integration of Notch and Smad1/5 signaling cascades. Dev. Cell 22, 501-514. https://doi.org/10.1016/j.devcel.2012.01.007
  26. Muller, F., Blader, P., Rastegar, S., Fischer, N., Knochel, W., and Strahle, U. (1999). Characterization of zebrafish smad1, smad2 and smad5: the amino-terminus of smad1 and smad5 is required for specific function in the embryo. Mech. Dev. 88, 73-88. https://doi.org/10.1016/S0925-4773(99)00173-2
  27. Roman, B.L., Pham, V.N., Lawson, N.D., Kulik, M., Childs, S., Lekven, A.C., Garrity, D.M., Moon, R.T., Fishman, M.C., Lechleider, R.J., et al. (2002). Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels. Development 129, 3009-3019.
  28. Schmitt, C.E., Woolls, M.J., and Jin, S.W. (2013). Mutant-specific gene expression profiling identifies SRY-related HMG box 11b (SOX11b) as a novel regulator of vascular development in zebrafish. Mol. Cells 35, 166-172. https://doi.org/10.1007/s10059-013-2307-8
  29. Sieber, C., Kopf, J., Hiepen, C., and Knaus, P. (2009). Recent advances in BMP receptor signaling. Cytokine Growth Factor Rev. 20, 343-355. https://doi.org/10.1016/j.cytogfr.2009.10.007
  30. Wakefield, L.M., and Hill, C.S. (2013). Beyond $TGF\beta$: roles of other $TGF\beta$ superfamily members in cancer. Nat. Rev. Cancer 13, 328-341. https://doi.org/10.1038/nrc3500
  31. Wiley, D.M., and Jin, S.W. (2011). Bone Morphogenetic Protein functions as a context-dependent angiogenic cue in vertebrates. Semin. Cell Dev. Biol. 22, 1012-1018. https://doi.org/10.1016/j.semcdb.2011.10.005
  32. Wiley, D.M., Kim, J.D., Hao, J., Hong, C.C., Bautch, V.L., and Jin, S.W. (2011). Distinct signalling pathways regulate sprouting angiogenesis from the dorsal aorta and the axial vein. Nat. Cell Biol. 13, 686-692. https://doi.org/10.1038/ncb2232
  33. Yaniv, K., Isogai, S., Castranova, D., Dye, L., Hitomi, J., and Weinstein, B.M. (2006). Live imaging of lymphatic development in the zebrafish. Nat. Med. 12, 711-716. https://doi.org/10.1038/nm1427
  34. Yoshimatsu, Y., Lee, Y.G., Akatsu, Y., Taguchi, L., Suzuki, H.I., Cunha, S.I., Maruyama, K., Suzuki, Y., Yamazaki, T., Katsura, A., et al. (2013). Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression. Proc. Natl. Acad. Sci. USA 110, 18940-18945. https://doi.org/10.1073/pnas.1310479110

Cited by

  1. BMP signaling in vascular biology and dysfunction vol.27, 2016, https://doi.org/10.1016/j.cytogfr.2015.12.005
  2. A Tale of Two Models: Mouse and Zebrafish as Complementary Models for Lymphatic Studies vol.37, pp.7, 2014, https://doi.org/10.14348/molcells.2014.0108
  3. Zebrafish Crip2 Plays a Critical Role in Atrioventricular Valve Development by Downregulating the Expression of ECM Genes in the Endocardial Cushion vol.37, pp.5, 2014, https://doi.org/10.14348/molcells.2014.0072
  4. Fipronil-induced enantioselective developmental toxicity to zebrafish embryo-larvae involves changes in DNA methylation vol.7, pp.1, 2017, https://doi.org/10.1038/s41598-017-02255-5
  5. Development of the lymphatic system: new questions and paradigms vol.143, pp.6, 2016, https://doi.org/10.1242/dev.132431
  6. Bone Morphogenetic Proteins in Vascular Homeostasis and Disease vol.10, pp.2, 2017, https://doi.org/10.1101/cshperspect.a031989
  7. Venous identity requires BMP signalling through ALK3 vol.10, pp.1, 2019, https://doi.org/10.1038/s41467-019-08315-w
  8. Identification of a rare BMP pathway mutation in a non-syndromic human brain arteriovenous malformation via exome sequencing vol.5, pp.None, 2018, https://doi.org/10.1038/hgv.2018.1
  9. Prioritization of genes involved in endothelial cell apoptosis by their implication in lymphedema using an analysis of associative gene networks with ANDSystem vol.12, pp.2, 2019, https://doi.org/10.1186/s12920-019-0492-9
  10. The BMP Pathway in Blood Vessel and Lymphatic Vessel Biology vol.22, pp.12, 2014, https://doi.org/10.3390/ijms22126364