Hippo Signaling Circuit and Divergent Tissue Growth in Mammalian Eye

  • Moon, Kyeong Hwan (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Kim, Jin Woo (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST))
  • Received : 2018.03.02
  • Accepted : 2018.03.22
  • Published : 2018.04.30


Vertebrate organ development is accompanied by demarcation of tissue compartments, which grow coordinately with their neighbors. Hence, perturbing the coordinative growth of neighboring tissue compartments frequently results in organ malformation. The growth of tissue compartments is regulated by multiple intercellular and intracellular signaling pathways, including the Hippo signaling pathway that limits the growth of various organs. In the optic neuroepithelial continuum, which is partitioned into the retina, retinal pigment epithelium (RPE) and ciliary margin (CM) during eye development, the Hippo signaling activity operates differentially, as it does in many tissues. In this review, we summarize recent studies that have explored the relationship between the Hippo signaling pathway and growth of optic neuroepithelial compartments. We will focus particularly on the roles of a tumor suppressor, neurofibromin 2 (NF2), whose expression is not only dependent on compartment-specific transcription factors, but is also subject to regulation by a Hippo-Yap feedback signaling circuit.


Supported by : National Research Foundation of Korea


  1. Akhmametyeva, E.M., Mihaylova, M.M., Luo, H., Kharzai, S., Welling, D.B., and Chang, L.S. (2006). Regulation of the neurofibromatosis 2 gene promoter expression during embryonic development. Dev. Dyn. 235, 2771-2785.
  2. Asaoka, Y., Hata, S., Namae, M., Furutani-Seiki, M., and Nishina, H. (2014). The Hippo pathway controls a switch between retinal progenitor cell proliferation and photoreceptor cell differentiation in zebrafish. PLoS ONE 9, e97365.
  3. Asthagiri, A.R., Parry, D.M., Butman, J.A., Kim, H.J., Tsilou, E.T., Zhuang, Z., and Lonser, R.R. (2009). Neurofibromatosis type 2. Lancet 373, 1974-1986.
  4. Barry, E.R., Morikawa, T., Butler, B.L., Shrestha, K., de la Rosa, R., Yan, K.S., Fuchs, C.S., Magness, S.T., Smits, R., Ogino, S., et al. (2013). Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature 493, 106-110.
  5. Basu-Roy, U., Bayin, N.S., Rattanakorn, K., Han, E., Placantonakis, D.G., Mansukhani, A., and Basilico, C. (2015). Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells. Nat. Comm. 6, 6411.
  6. Beebe, D.C. (1986). Development of the ciliary body: a brief review. Transact. Ophthal. Soc. U. K. 105, 123-130.
  7. Belanger, M.C., Robert, B., and Cayouette, M. (2017). Msx1-Positive Progenitors in the Retinal Ciliary Margin Give Rise to Both Neural and Non-neural Progenies in Mammals. Dev. Cell 40, 137-150.
  8. Bennett, F.C., and Harvey, K.F. (2006). Fat cadherin modulates organ size in Drosophila via the Salvador/Warts/Hippo signaling pathway. Curr. Biol. 16, 2101-2110.
  9. Bosch, M.M., Boltshauser, E., Harpes, P., and Landau, K. (2006a). Ophthalmologic findings and long-term course in patients with neurofibromatosis type 2. Am. J. Ophthal. 141, 1068-1077.
  10. Bosch, M.M., Wichmann, W.W., Boltshauser, E., and Landau, K. (2006b). Optic nerve sheath meningiomas in patients with neurofibromatosis type 2. Arc. Ophthal. 124, 379-385.
  11. Bretscher, A., Edwards, K., and Fehon, R.G. (2002). ERM proteins and merlin: integrators at the cell cortex. Nat. Rev. Mol. Cell Biol. 3, 586-599.
  12. Cabochette, P., Vega-Lopez, G., Bitard, J., Parain, K., Chemouny, R., Masson, C., Borday, C., Hedderich, M., Henningfeld, K.A., Locker, M., et al. (2015). YAP controls retinal stem cell DNA replication timing and genomic stability. eLife 4, e08488.
  13. Chan, S.W., Lim, C.J., Chong, Y.F., Pobbati, A.V., Huang, C., and Hong, W. (2011). Hippo pathway-independent restriction of TAZ and YAP by angiomotin. J. Biol. Chem. 286, 7018-7026.
  14. Chang, B., Smith, R.S., Peters, M., Savinova, O.V., Hawes, N.L., Zabaleta, A., Nusinowitz, S., Martin, J.E., Davisson, M.L., Cepko, C.L., et al. (2001). Haploinsufficient Bmp4 ocular phenotypes include anterior segment dysgenesis with elevated intraocular pressure. BMC Genet. 2, 18.
  15. Cho, E., and Irvine, K.D. (2004). Action of fat, four-jointed, dachsous and dachs in distal-to-proximal wing signaling. Development 131, 4489-4500.
  16. Cho, S.H., and Cepko, C.L. (2006). Wnt2b/beta-catenin-mediated canonical Wnt signaling determines the peripheral fates of the chick eye. Development 133, 3167-3177.
  17. Chow, R.L., and Lang, R.A. (2001). Early eye development in vertebrates. Ann. Rev. Cell Dev. Biol. 17, 255-296.
  18. Christ, A., Christa, A., Klippert, J., Eule, J.C., Bachmann, S., Wallace, V.A., Hammes, A., and Willnow, T.E. (2015). LRP2 acts as SHH clearance receptor to protect the retinal margin from mitogenic stimuli. Dev. Cell 35, 36-48.
  19. Cicero, S.A., Johnson, D., Reyntjens, S., Frase, S., Connell, S., Chow, L.M., Baker, S.J., Sorrentino, B.P., and Dyer, M.A. (2009). Cells previously identified as retinal stem cells are pigmented ciliary epithelial cells. Proc. Natl. Acad. Sci. U SA 106, 6685-6690.
  20. Curto, M., Cole, B.K., Lallemand, D., Liu, C.-H., and McClatchey, A.I. (2007). Contact-dependent inhibition of EGFR signaling by Nf2/Merlin. J. Cell Biol. 177, 893-903.
  21. Curto, M., and McClatchey, A.I. (2007). Nf2/Merlin: a coordinator of receptor signalling and intercellular contact. Br. J. Cancer 98, 256-262.
  22. Fuhrmann, S., Riesenberg, A.N., Mathiesen, A.M., Brown, E.C., Vetter, M.L., and Brown, N.L. (2009). Characterization of a transient TCF/LEF-responsive progenitor population in the embryonic mouse retina. Invest. Ophthal. Vis. Sci. 50, 432-440.
  23. Fuhrmann, S., Zou, C., and Levine, E.M. (2014). Retinal pigment epithelium development, plasticity, and tissue homeostasis. Exp. Eye Res. 123, 141-150.
  24. Fujimura, N., Taketo, M.M., Mori, M., Korinek, V., and Kozmik, Z. (2009). Spatial and temporal regulation of Wnt/${\beta}$-catenin signaling is essential for development of the retinal pigment epithelium. Dev. Biol. 334, 31-45.
  25. Graw, J. (2010). Eye development. Curr. Top. Dev. Biol. 90, 343-386.
  26. Grzeschik, N.A., Parsons, L.M., Allott, M.L., Harvey, K.F., and Richardson, H.E. (2010). Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr. Biol. 20, 573-581.
  27. Ha, T., Moon, K.H., Dai, L., Hatakeyama, J., Yoon, K., Park, H.S., Kong, Y.Y., Shimamura, K., and Kim, J.W. (2017). The Retinal Pigment Epithelium Is a Notch Signaling Niche in the Mouse Retina. Cell Rep. 19, 351-363.
  28. Hamaratoglu, F., Willecke, M., Kango-Singh, M., Nolo, R., Hyun, E., Tao, C., Jafar-Nejad, H., and Halder, G. (2006). The tumoursuppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat. Cell Biol. 8, 27-36.
  29. Harvey, K.F., Pfleger, C.M., and Hariharan, I.K. (2003). The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114, 457-467.
  30. Huang, J., Wu, S., Barrera, J., Matthews, K., and Pan, D. (2005). The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell 122, 421-434.
  31. Huang, J.M., Nagatomo, I., Suzuki, E., Mizuno, T., Kumagai, T., Berezov, A., Zhang, H., Karlan, B., Greene, M.I., and Wang, Q. (2013). YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14. Oncogene 32, 2220-2229.
  32. Kanai, F., Marignani, P.A., Sarbassova, D., Yagi, R., Hall, R.A., Donowitz, M., Hisaminato, A., Fujiwara, T., Ito, Y., Cantley, L.C., et al. (2000). TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J. 19, 6778-6791.
  33. Kim, H.T., and Kim, J.W. (2012). Compartmentalization of vertebrate optic neuroephithelium: external cues and transcription factors. Mol. Cells 33, 317-324.
  34. Kim, J.Y., Park, R., Lee, J.H., Shin, J., Nickas, J., Kim, S., and Cho, S.H. (2016). Yap is essential for retinal progenitor cell cycle progression and RPE cell fate acquisition in the developing mouse eye. Dev. Biol. 419, 336-347.
  35. Kim, N.G., Koh, E., Chen, X., and Gumbiner, B.M. (2011). E-cadherin mediates contact inhibition of proliferation through Hippo signalingpathway components. P Proc. Natl. Acad. Sci. USA 108, 11930-11935.
  36. Lai, Z.C., Wei, X., Shimizu, T., Ramos, E., Rohrbaugh, M., Nikolaidis, N., Ho, L.L., and Li, Y. (2005). Control of cell proliferation and apoptosis by mob as tumor suppressor, mats. Cell 120, 675-685.
  37. Landau, K., and Yasargil, G.M. (1993). Ocular fundus in neurofibromatosis type 2. Br. J. Ophthal. 77, 646-649.
  38. Lavado, A., He, Y., Pare, J., Neale, G., Olson, E.N., Giovannini, M., and Cao, X. (2013). Tumor suppressor Nf2 limits expansion of the neural progenitor pool by inhibiting Yap/Taz transcriptional coactivators. Development 140, 3323-3334.
  39. Li, W., You, L., Cooper, J., Schiavon, G., Pepe-Caprio, A., Zhou, L., Ishii, R., Giovannini, M., Hanemann, C.O., Long, S.B., et al. (2010). Merlin/NF2 suppresses tumorigenesis by inhibiting the E3 ubiquitin ligase CRL4(DCAF1) in the nucleus. Cell 140, 477-490.
  40. Li, W., Cooper, J., Karajannis, M.A., and Giancotti, F.G. (2012). Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus. EMBO Rep. 13, 204-215.
  41. Li, Y., Zhou, H., Li, F., Chan, S.W., Lin, Z., Wei, Z., Yang, Z., Guo, F., Lim, C.J., Xing, W., et al. (2015). Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway. Cell Res. 25, 801-817.
  42. Lian, I., Kim, J., Okazawa, H., Zhao, J., Zhao, B., Yu, J., Chinnaiyan, A., Israel, M.A., Goldstein, L.S., Abujarour, R., et al. (2010). The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes Dev. 24, 1106-1118.
  43. Liu, H., Mohamed, O., Dufort, D., and Wallace, V.A. (2003). Characterization of Wnt signaling components and activation of the Wnt canonical pathway in the murine retina. Dev. Dyn. 227, 323-334.
  44. Liu, H., Xu, S., Wang, Y., Mazerolle, C., Thurig, S., Coles, B.L.K., Ren, J.C., Taketo, M.M., van der Kooy, D., and Wallace, V.A. (2007). Ciliary margin transdifferentiation from neural retina is controlled by canonical Wnt signaling. Dev. Biol. 308, 54-67.
  45. Liu, X., Yang, N., Figel, S.A., Wilson, K.E., Morrison, C.D., Gelman, I.H., and Zhang, J. (2013). PTPN14 interacts with and negatively regulates the oncogenic function of YAP. Oncogene 32, 1266-1273.
  46. Marcucci, F., Murcia-Belmonte, V., Coca, Y., Ferreiro-Galve, S., Wang, Q., Kuwajima, T., Khalid, S., Ross, M.E., Herrera, E., and Mason, C. (2016). The ciliary margin zone of the mammalian retina generates retinal ganglion cells. Cell Rep. 17, 3153-3164.
  47. McLaughlin, M.E., Pepin, S.M., Maccollin, M., Choopong, P., and Lessell, S. (2007). Ocular pathologic findings of neurofibromatosis type 2. Arc. Ophthal. 125, 389-394.
  48. Miesfeld, J.B., Gestri, G., Clark, B.S., Flinn, M.A., Poole, R.J., Bader, J.R., Besharse, J.C., Wilson, S.W., and Link, B.A. (2015). Yap and Taz regulate retinal pigment epithelial cell fate. Development 142, 3021-3032.
  49. Mohseni, M., Sun, J., Lau, A., Curtis, S., Goldsmith, J., Fox, V.L., Wei, C., Frazier, M., Samson, O., Wong, K.K., et al. (2014). A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway. Nat. Cell Biol. 16, 108-117.
  50. Mononen, T.K., K.; Tuppurainen, K. (2007). Colobomatous microphthalmia and a cyst associated with a nonsense NF2 gene mutation. Am. Genet. Soc. f20750.
  51. Moon, K.H., Kim, H.T., Lee, D., Rao, M.B., Levine, E.M., Lim, D.S., and Kim, J.W. (2018). Differential Expression of NF2 in Neuroepithelial Compartments Is Necessary for Mammalian Eye Development. Dev. Cell 44, 13-28 e13.
  52. Moroishi, T., Park, H.W., Qin, B., Chen, Q., Meng, Z., Plouffe, S.W., Taniguchi, K., Yu, F.X., Karin, M., Pan, D., et al. (2015). A YAP/TAZ induced feedback mechanism regulates Hippo pathway homeostasis. Genes Dev. 29, 1271-1284.
  53. Napier, H.R.L., and Kidson, S.H. (2005). Proliferation and cell shape changes during ciliary body morphogenesis in the mouse. Dev. Dyn. 233, 213-223.
  54. Ohgushi, M., Minaguchi, M., and Sasai, Y. (2015). Rho-Signaling-Directed YAP/TAZ Activity Underlies the Long-Term Survival and Expansion of Human Embryonic Stem Cells. Cell Stem Cell 17, 448-461.
  55. Ohta, K., Ito, A., and Tanaka, H. (2008). Neuronal stem/progenitor cells in the vertebrate eye. Dev. Growth Diff. 50, 253-259.
  56. Robinson, B.S., Huang, J., Hong, Y., and Moberg, K.H. (2010). Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded. Curr. Biol. 20, 582-590.
  57. Schlegelmilch, K., Mohseni, M., Kirak, O., Pruszak, J., Rodriguez, J.R., Zhou, D., Kreger, B.T., Vasioukhin, V., Avruch, J., Brummelkamp, T.R., et al. (2011). Yap1 acts downstream of alpha-catenin to control epidermal proliferation. Cell 144, 782-795.
  58. Serinagaoglu, Y., Pare, J., Giovannini, M., and Cao, X. (2015). Nf2-Yap signaling controls the expansion of DRG progenitors and glia during DRG development. Dev. Biol. 398, 97-109.
  59. Sivalingam, A., Augsburger, J., Perilongo, G., Zimmerman, R., and Barabas, G. (1991). Combined hamartoma of the retina and retinal pigment epithelium in a patient with neurofibromatosis type 2. J. Ped. Ophthal. Strabis. 28, 320-322.
  60. Song, J.Y., Park, R., Kim, J.Y., Hughes, L., Lu, L., Kim, S., Johnson, R.L., and Cho, S.H. (2014). Dual function of Yap in the regulation of lens progenitor cells and cellular polarity. Dev. Biol. 386, 281-290.
  61. St John, M.A., Tao, W., Fei, X., Fukumoto, R., Carcangiu, M.L., Brownstein, D.G., Parlow, A.F., McGrath, J., and Xu, T. (1999). Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nat. Genet. 21, 182-186.
  62. Stanger, B.Z. (2008). Organ size determination and the limits of regulation. Cell Cycle 7, 318-324.
  63. Sudol, M. (1994). Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes protooncogene product. Oncogene 9, 2145-2152.
  64. Tapon, N., Harvey, K.F., Bell, D.W., Wahrer, D.C., Schiripo, T.A., Haber, D., and Hariharan, I.K. (2002). salvador Promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110, 467-478.
  65. Tropepe, V., Coles, B.L., Chiasson, B.J., Horsford, D.J., Elia, A.J., McInnes, R.R., and van der Kooy, D. (2000). Retinal stem cells in the adult mammalian eye. Science 287, 2032-2036.
  66. Udan, R.S., Kango-Singh, M., Nolo, R., Tao, C., and Halder, G. (2003). Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nat. Cell Biol. 5, 914-920.
  67. Verghese, S., Waghmare, I., Kwon, H., Hanes, K., and Kango-Singh, M. (2012). Scribble acts in the Drosophila fat-hippo pathway to regulate warts activity. PLoS ONE 7, e47173.
  68. Wang, Y., Dakubo, G.D., Thurig, S., Mazerolle, C.J., and Wallace, V.A. (2005). Retinal ganglion cell-derived sonic hedgehog locally controls proliferation and the timing of RGC development in the embryonic mouse retina. Development 132, 5103-5113.
  69. Westenskow, P., Piccolo, S., and Fuhrmann, S. (2009). Beta-catenin controls differentiation of the retinal pigment epithelium in the mouse optic cup by regulating Mitf and Otx2 expression. Development 136, 2505-2510.
  70. Wiley, L.A., Dattilo, L.K., Kang, K.B., Giovannini, M., and Beebe, D.C. (2010). The Tumor Suppressor Merlin Is Required for Cell Cycle Exit, Terminal Differentiation, and Cell Polarity in the Developing Murine Lens. Invest. Ophthal. Vis. Sci. 51, 3611-3618.
  71. Wu, S., Huang, J., Dong, J., and Pan, D. (2003). hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell 114, 445-456.
  72. Yu, F.X., and Guan, K.L. (2013). The Hippo pathway: regulators and regulations. Genes Dev. 27, 355-371.
  73. Yue, T., Tian, A., and Jiang, J. (2012). The cell adhesion molecule echinoid functions as a tumor suppressor and upstream regulator of the Hippo signaling pathway. Dev. Cell 22, 255-267.
  74. Zhang, N., Bai, H., David, K.K., Dong, J., Zheng, Y., Cai, J., Giovannini, M., Liu, P., Anders, R.A., and Pan, D. (2010). The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell 19, 27-38.
  75. Zhang, H., Deo, M., Thompson, R.C., Uhler, M.D., and Turner, D.L. (2012). Negative regulation of Yap during neuronal differentiation. Dev. Biol. 361, 103-115.
  76. Zhao, S., Chen, Q., Hung, F.C., and Overbeek, P.A. (2002). BMP signaling is required for development of the ciliary body. Development 129, 4435-4442.
  77. Zhou, Y., Tanzie, C., Yan, Z., Chen, S., Duncan, M., Gaudenz, K., Li, H., Seidel, C., Lewis, B., Moran, A., et al. (2013). Notch2 regulates BMP signaling and epithelial morphogenesis in the ciliary body of the mouse eye. Proc. Natl. Acad. Sci. USA 110, 8966-8971.