Volume 11 Issue 6
May  2020
Turn off MathJax
Article Contents
Xueyu Li, Qiang Lu, Yuanyuan Peng, Fang Geng, Xuelian Shao, Huili Zhou, Ying Cao, Ruilin Zhang. Primary cilia mediate Klf2-dependant Notch activation in regenerating heart[J]. Protein&Cell, 2020, 11(6): 433-445. doi: 10.1007/s13238-020-00695-w
Citation: Xueyu Li, Qiang Lu, Yuanyuan Peng, Fang Geng, Xuelian Shao, Huili Zhou, Ying Cao, Ruilin Zhang. Primary cilia mediate Klf2-dependant Notch activation in regenerating heart[J]. Protein&Cell, 2020, 11(6): 433-445. doi: 10.1007/s13238-020-00695-w

Primary cilia mediate Klf2-dependant Notch activation in regenerating heart

doi: 10.1007/s13238-020-00695-w
Funds:

This study was supported by National Key R&D Program of China grant 2018YFA0801004 and NSFC grant 31571492 to R.Z.

  • Received Date: 2019-12-20
  • Rev Recd Date: 2020-02-07
  • Unlike adult mammalian heart, zebrafish heart has a remarkable capacity to regenerate after injury. Previous study has shown Notch signaling activation in the endocardium is essential for regeneration of the myocardium and this activation is mediated by hemodynamic alteration after injury, however, the molecular mechanism has not been fully explored. In this study we demonstrated that blood flow change could be perceived and transmitted in a primary cilia dependent manner to control the hemodynamic responsive klf2 gene expression and subsequent activation of Notch signaling in the endocardium. First we showed that both homologues of human gene KLF2 in zebrafish, klf2a and klf2b, could respond to hemodynamic alteration and both were required for Notch signaling activation and heart regeneration. Further experiments indicated that the upregulation of klf2 gene expression was mediated by endocardial primary cilia. Overall, our findings reveal a novel aspect of mechanical shear stress signal in activating Notch pathway and regulating cardiac regeneration.
  • loading
  • [1]
    Atkins GB, Jain MK (2007) Role of Kruppel-like transcription factors in endothelial biology. Circ Res 100(12):1686-1695
    [2]
    Austin-Tse C, Halbritter J, Zariwala MA, Gilberti RM, Gee HY, Hellman N, Pathak N, Liu Y, Panizzi JR, Patel-King RS et al(2013) Zebrafish ciliopathy screen plus human mutational analysis identifies C21orf59 and CCDC65 defects as causing primary ciliary dyskinesia. Am J Hum Genet 93(4):672-686
    [3]
    Baratchi S, Khoshmanesh K, Woodman OL, Potocnik S, Peter K, McIntyre P (2017) Molecular sensors of blood flow in endothelial cells. Trends Mol Med 23(9):850-868
    [4]
    Chang N, Sun C, Gao L, Zhu D, Xu X, Zhu X, Xiong J-W, Xi JJ (2013) Genome editing with RNA-guided Cas9 nuclease in zebrafish embryos. Cell Res 23(4):465-472
    [5]
    Clark BS, Cui S, Miesfeld JB, Klezovitch O, Vasioukhin V, Link BA (2012) Loss of Llgl1 in retinal neuroepithelia reveals links between apical domain size, Notch activity neurogenesis. Development 139(9):1599-1610
    [6]
    Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, Dubin AE, Patapoutian A (2010) Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330(6000):55-60
    [7]
    Dekker RJ, van Soest S, Fontijn RD, Salamanca S, de Groot PG, VanBavel E, Pannekoek H, Horrevoets AJ (2002) Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Krüppel-like factor (KLF2). Blood 100(5):1689-1698
    [8]
    Delling M, DeCaen PG, Doerner JF, Febvay S, Clapham DE (2013) Primary cilia are specialized calcium signalling organelles. Nature 504(7479):311
    [9]
    Egorova AD, Khedoe PP, Goumans MJ, Yoder BK, Nauli SM, ten Dijke P, Poelmann RE, Hierck BP (2011) Lack of primary cilia primes shear-induced endothelial-to-mesenchymal transition. Circ Res 108(9):1093-1101
    [10]
    Espinha LC, Hoey DA, Fernandes PR, Rodrigues HC, Jacobs CR (2014) Oscillatory fluid flow influences primary cilia and microtubule mechanics. Cytoskeleton 71(7):435-445
    [11]
    Felician G, Collesi C, Lusic M, Martinelli V, Ferro MD, Zentilin L, Zacchigna S, Giacca M (2014) Epigenetic modification at Notch responsive promoters blunts efficacy of inducing Notch pathway reactivation after myocardial infarction. Circ Res 115(7):636-641
    [12]
    Goddard LM, Duchemin AL, Ramalingan H, Wu B, Chen M, Bamezai S, Yang J, Li L, Morley MP, Wang T et al (2017) Hemodynamic forces sculpt developing heart valves through a KLF2-WNT9B paracrine signaling axis. Dev Cell 43(3):274-289
    [13]
    Gálvez-Santisteban M, Chen D, Zhang R, Serrano R, Nguyen C, Zhao L, Nerb L, Masutani EM, Vermot J, Burns CG et al (2019) Hemodynamic-mediated endocardial signaling controls in vivo myocardial reprogramming. eLife 8:e44816
    [14]
    Heckel E, Boselli F, Roth S, Krudewig A, Belting H-G, Charvin G, Vermot J (2015) Oscillatory flow modulates mechanosensitive klf2a expression through trpv4 and trpp2 during heart valve development. Curr Biol 25(10):1354-1361
    [15]
    Jin S-W, Beis D, Mitchell T, Chen J-N, Stainier DY (2005) Cellular and molecular analyses of vascular tube and lumen formation in zebrafish. Development 132(23):5199-5209
    [16]
    Jopling C, Sleep E, Raya M, Marti M, Raya A, Belmonte JCI (2010) Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464(7288):606
    [17]
    Kikuchi K, Holdway JE, Werdich AA, Anderson RM, Fang Y, Egnaczyk GF, Evans T, Macrae CA, Stainier DYR, Poss KD (2010) Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature 464(7288):601-605
    [18]
    Lee JS, Yu Q, Shin JT, Sebzda E, Bertozzi C, Chen M, Mericko P, Stadtfeld M, Zhou D, Cheng L et al (2006) Klf2 is an essential regulator of vascular hemodynamic forces in vivo. Dev Cell 11(6):845-857
    [19]
    Liu Z, Tu H, Kang Y, Xue Y, Ma D, Zhao C, Li H, Wang L, Liu F (2019) Primary cilia regulate hematopoietic stem and progenitor cell specification through Notch signaling in zebrafish. Nat Commun 10(1):1839
    [20]
    Mandal A, Holowiecki A, Song YC, Waxman JS (2017) Wnt signaling balances specification of the cardiac and pharyngeal muscle fields. Mech Dev 143:32-41
    [21]
    Munch J, Grivas D, Gonzalez-Rajal A, Torregrosa-Carrion R, de la Pompa JL (2017) Notch signalling restricts inflammation and serpine1 expression in the dynamic endocardium of the regenerating zebrafish heart. Development 144(8):1425-1440
    [22]
    Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AEH, Lu W, Brown EM, Quinn SJ et al (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33(2):129
    [23]
    Nauli SM, Kawanabe Y, Kaminski JJ, Pearce WJ, Ingber DE, Zhou J (2008) Endothelial cilia are fluid shear sensors that regulate calcium signaling and nitric oxide production through polycystin-1. Circulation 117(9):1161-1171
    [24]
    Nemir M, Metrich M, Plaisance I, Lepore M, Cruchet S, Berthonneche C, Sarre A, Radtke F, Pedrazzini T (2014) The Notch pathway controls fibrotic and regenerative repair in the adult heart. Eur Heart J 35(32):2174-2185
    [25]
    Nixon AM, Gunel M, Sumpio BE (2010) The critical role of hemodynamics in the development of cerebral vascular disease:a review. J Neurosurg 112(6):1240-1253
    [26]
    Oates AC, Pratt SJ, Vail B, Yan Y, Ho RK, Johnson SL, Postlethwait JH, Zon LI (2001) The zebrafish klf gene family. Blood 98(6):1792-1801
    [27]
    Orr AW, Helmke BP, Blackman BR, Schwartz MA (2006) Mechanisms of mechanotransduction. Dev Cell 10(1):11-20
    [28]
    Pazour GJ, Dickert BL, Vucica Y, Seeley ES, Rosenbaum JL, Witman GB, Cole DG (2000) Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J Cell Biol 151(3):709-718
    [29]
    Poss KD, Wilson LG, Keating MT (2002) Heart regeneration in zebrafish. Science 298(5601):2188-2190
    [30]
    Rasouli SJ, El-Brolosy M, Tsedeke AT, Bensimon-Brito A, Ghanbari P, Maischein HM, Kuenne C, Stainier DY (2018) The flow responsive transcription factor Klf2 is required for myocardial wall integrity by modulating Fgf signaling. eLife 7:e38889
    [31]
    Raya A, Koth CM, Büscher D, Kawakami Y, Itoh T, Raya RM, Sternik G, Tsai H-J, Rodríguez-Esteban C, Izpisúa-Belmonte JC (2003) Activation of Notch signaling pathway precedes heart regeneration in zebrafish. Proc Natl Acad Sci USA 100(Suppl 1):11889-11895
    [32]
    Rohatgi R, Milenkovic L, Scott MP (2007) Patched1 regulates hedgehog signaling at the primary cilium. Science 317(5836):372-376
    [33]
    Samsa LA, Givens C, Tzima E, Stainier DY, Qian L, Liu J (2015) Cardiac contraction activates endocardial Notch signaling to modulate chamber maturation in zebrafish. Development 142(23):4080-4091
    [34]
    Steed E, Faggianelli N, Roth S, Ramspacher C, Concordet J-P, Vermot J (2016) klf2a couples mechanotransduction and zebrafish valve morphogenesis through fibronectin synthesis. Nat Commun 7:11646
    [35]
    Thygesen K, Alpert JS, White HD (2007) Universal definition of myocardial infarction. J Am Coll Cardiol 50(22):2173-2195
    [36]
    Vermot J, Forouhar AS, Liebling M, Wu D, Plummer D, Gharib M, Fraser SE (2009) Reversing blood flows act through klf2a to ensure normal valvulogenesis in the developing heart. PLoS Biol 7(11):e1000246
    [37]
    Villalobos E, Criollo A, Schiattarella GG, Altamirano F, French KM, May HI, Jiang N, Nguyen NUN, Romero D, Roa JC et al (2019) Fibroblast primary cilia are required for cardiac fibrosis. Circulation 139:2342-2357
    [38]
    Zhang R, Han P, Yang H, Ouyang K, Lee D, Lin YF, Ocorr K, Kang G, Chen J, Stainier DY et al (2013) In vivo cardiac reprogramming contributes to zebrafish heart regeneration. Nature 498(7455):497-501
    [39]
    Zhao L, Ben-Yair R, Burns CE, Burns CG (2019) Endocardial Notch signaling promotes cardiomyocyte proliferation in the regenerating zebrafish heart through Wnt pathway antagonism. Cell Rep 26(3):546-554
    [40]
    Zhao L, Borikova AL, Ben-Yair R, Guner-Ataman B, MacRae CA, Lee RT, Burns CG, Burns CE (2014) Notch signaling regulates cardiomyocyte proliferation during zebrafish heart regeneration. Proc Natl Acad Sci USA 111(4):1403-1408
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(1)

    Article Metrics

    Article views (750) PDF downloads(155) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return