메뉴 건너뛰기




Volumn 19, Issue 4, 2004, Pages 225-230

Cystic kidney diseases: All roads lead to the cilium

Author keywords

[No Author keywords available]

Indexed keywords

EUKARYOTIC FLAGELLUM; GENE MUTATION; HUMAN; KIDNEY FAILURE; KIDNEY POLYCYSTIC DISEASE; NONHUMAN; PATHOGENESIS; PROTEIN LOCALIZATION; REVIEW; ANIMAL; EPITHELIUM CELL; GENETICS; KIDNEY TUBULE; PATHOLOGY; ULTRASTRUCTURE;

EID: 4544287005     PISSN: 15489213     EISSN: None     Source Type: Journal    
DOI: 10.1152/physiol.00003.2004     Document Type: Review
Times cited : (77)

References (85)
  • 1
    • 0037642424 scopus 로고    scopus 로고
    • Nephronophthisis and medullar cystic disease: Genetic aspects
    • Alvarez Martinez V and Goto E. Nephronophthisis and medullar cystic disease: genetic aspects. Nefrologia 23, Suppl 1: 46-51, 2003.
    • (2003) Nefrologia , vol.23 , Issue.1 SUPPL. , pp. 46-51
    • Alvarez Martinez, V.1    Goto, E.2
  • 3
    • 0035127256 scopus 로고    scopus 로고
    • Molecular genetics and pathogenesis of autosomal dominant polycystic kidney disease
    • Arnaout MA. Molecular genetics and pathogenesis of autosomal dominant polycystic kidney disease. Annu Rev Med 52: 93-123, 2001.
    • (2001) Annu Rev Med , vol.52 , pp. 93-123
    • Arnaout, M.A.1
  • 4
    • 0027238893 scopus 로고
    • Juvenile cystic kidneys (jck): A new mouse mutation which causes polycystic kidneys
    • Atala A, Freeman MR, Mandell J, and Beier DR. Juvenile cystic kidneys (jck): a new mouse mutation which causes polycystic kidneys. Kidney Int 43: 1081-1085, 1993.
    • (1993) Kidney Int , vol.43 , pp. 1081-1085
    • Atala, A.1    Freeman, M.R.2    Mandell, J.3    Beier, D.R.4
  • 8
    • 0035834136 scopus 로고    scopus 로고
    • Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene
    • Boulter C, Mulroy S, Webb S, Fleming S, Brindle K, and Sandford R. Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene. Proc Natl Acad Sci USA 98: 12174-12179, 2001.
    • (2001) Proc Natl Acad Sci USA , vol.98 , pp. 12174-12179
    • Boulter, C.1    Mulroy, S.2    Webb, S.3    Fleming, S.4    Brindle, K.5    Sandford, R.6
  • 9
    • 0034725792 scopus 로고    scopus 로고
    • Localization of 5-HT(6) receptors at the plasma membrane of neuronal cilia in the rat brain
    • Brailov I, Bancila M, Brisorgueil M, Miquel M, Hamon M, and Verge D. Localization of 5-HT(6) receptors at the plasma membrane of neuronal cilia in the rat brain. Brain Res 872: 271-275, 2000.
    • (2000) Brain Res , vol.872 , pp. 271-275
    • Brailov, I.1    Bancila, M.2    Brisorgueil, M.3    Miquel, M.4    Hamon, M.5    Verge, D.6
  • 10
    • 0035899903 scopus 로고    scopus 로고
    • The bld1 mutation identifies the Chlamydomonas osm-6 homolog as a gene required for flagellar assembly
    • Brazelton WJ, Amundsen CD, Silflow CD, and Lefebvre PA. The bld1 mutation identifies the Chlamydomonas osm-6 homolog as a gene required for flagellar assembly. Curr Biol 11: 1591-1594, 2001.
    • (2001) Curr Biol , vol.11 , pp. 1591-1594
    • Brazelton, W.J.1    Amundsen, C.D.2    Silflow, C.D.3    Lefebvre, P.A.4
  • 11
    • 0025980486 scopus 로고
    • Turning on and turning off the sense of smell
    • Burchell B. Turning on and turning off the sense of smell. Nature 350: 16-17, 1991.
    • (1991) Nature , vol.350 , pp. 16-17
    • Burchell, B.1
  • 13
    • 0027232194 scopus 로고
    • Polycystic kidney disease: Primary extracellular matrix abnormality or defective cellular differentiation?
    • Calvet JP. Polycystic kidney disease: primary extracellular matrix abnormality or defective cellular differentiation? Kidney Int 43: 101-108, 1993.
    • (1993) Kidney Int , vol.43 , pp. 101-108
    • Calvet, J.P.1
  • 14
    • 0025089548 scopus 로고
    • Congenital hepatic fibrosis in autosomal-dominant polycystic kidney disease
    • Cobben JM, Breuning MH, Schoots C, ten Kate LP, and Zerres K. Congenital hepatic fibrosis in autosomal-dominant polycystic kidney disease. Kidney Int 38: 880-885, 1990.
    • (1990) Kidney Int , vol.38 , pp. 880-885
    • Cobben, J.M.1    Breuning, M.H.2    Schoots, C.3    Ten Kate, L.P.4    Zerres, K.5
  • 16
    • 0031750484 scopus 로고    scopus 로고
    • Chlamydomonas kinesin-II-dependent intraflagellar transport (IFT): IFT particles contain proteins required for ciliary assembly in Caenorhabditis elegans sensory neurons
    • Cole DG, Diener DR, Himelblau AL, Beech PL, Fuster JC, and Rosenbaum JL. Chlamydomonas kinesin-II-dependent intraflagellar transport (IFT): IFT particles contain proteins required for ciliary assembly in Caenorhabditis elegans sensory neurons. J Cell Biol 141: 993-1008, 1998.
    • (1998) J Cell Biol , vol.141 , pp. 993-1008
    • Cole, D.G.1    Diener, D.R.2    Himelblau, A.L.3    Beech, P.L.4    Fuster, J.C.5    Rosenbaum, J.L.6
  • 17
    • 0023465369 scopus 로고
    • Elevated c-myc protooncogene expression in autosomal recessive polycystic kidney disease
    • Corrigendum. Proc Natl Acad Sci USA 85: April 1988, p. 2578
    • Cowley BD Jr, Smardo FL Jr, Grantham JJ, and Calvet JP. Elevated c-myc protooncogene expression in autosomal recessive polycystic kidney disease. Proc Natl Acad Sci USA 84: 8394-8398, 1987. [Corrigendum. Proc Natl Acad Sci USA 85: April 1988, p. 2578].
    • (1987) Proc Natl Acad Sci USA , vol.84 , pp. 8394-8398
    • Cowley Jr., B.D.1    Smardo Jr., F.L.2    Grantham, J.J.3    Calvet, J.P.4
  • 18
    • 0028278058 scopus 로고
    • The polycystic kidney disease gene 1 encodes a 14 kb transcript and lies within a duplicated region on chromosome 16
    • European Polycystic Kidney Disease Consortium. The polycystic kidney disease gene 1 encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 77: 881-894, 1994.
    • (1994) Cell , vol.77 , pp. 881-894
  • 19
    • 0030857293 scopus 로고    scopus 로고
    • Oral-facial-digital syndrome type 1 is another dominant polycystic kidney disease: Clinical, radiological and histopathological features of a new kindred
    • Feather SA, Winyard PJ, Dodd S, and Woolf AS. Oral-facial-digital syndrome type 1 is another dominant polycystic kidney disease: clinical, radiological and histopathological features of a new kindred. Nephrol Dial Transplant 12: 1354-1361, 1997.
    • (1997) Nephrol Dial Transplant , vol.12 , pp. 1354-1361
    • Feather, S.A.1    Winyard, P.J.2    Dodd, S.3    Woolf, A.S.4
  • 20
    • 0030876936 scopus 로고    scopus 로고
    • The oral-facial-digital syndrome type 1 (OFD1), a cause of polycystic kidney disease and associated malformations, maps to Xp22.2-Xp22.3
    • Feather SA, Woolf AS, Donnai D, Malcolm S, and Winter RM. The oral-facial-digital syndrome type 1 (OFD1), a cause of polycystic kidney disease and associated malformations, maps to Xp22.2-Xp22.3. Hum Mol Genet 6: 1163-1167, 1997.
    • (1997) Hum Mol Genet , vol.6 , pp. 1163-1167
    • Feather, S.A.1    Woolf, A.S.2    Donnai, D.3    Malcolm, S.4    Winter, R.M.5
  • 21
    • 0038700741 scopus 로고    scopus 로고
    • Characterization of the OFD1/Ofd1 genes on the human and mouse sex chromosomes and exclusion of Ofd1 for the Xpl mouse mutant
    • Ferrante MI, Barra A, Truong JP, Banfi S, Disteche CM, and Franco B. Characterization of the OFD1/Ofd1 genes on the human and mouse sex chromosomes and exclusion of Ofd1 for the Xpl mouse mutant. Genomics 81: 560-569, 2003.
    • (2003) Genomics , vol.81 , pp. 560-569
    • Ferrante, M.I.1    Barra, A.2    Truong, J.P.3    Banfi, S.4    Disteche, C.M.5    Franco, B.6
  • 24
    • 0242582130 scopus 로고    scopus 로고
    • Murine models of polycystic kidney disease: Molecular and therapeutic insights
    • Guay-Woodford LM. Murine models of polycystic kidney disease: molecular and therapeutic insights. Am J Physiol Renal Physiol 285: F1034-F1049, 2003.
    • (2003) Am J Physiol Renal Physiol , vol.285
    • Guay-Woodford, L.M.1
  • 28
    • 0034987372 scopus 로고    scopus 로고
    • The C. elegans homolog of the murine cystic kidney disease gene Tg737 functions in a ciliogenic pathway and is disrupted in osm-5 mutant worms
    • Haycraft CJ, Swoboda P, Taulman PD, Thomas JH, and Yoder BK. The C. elegans homolog of the murine cystic kidney disease gene Tg737 functions in a ciliogenic pathway and is disrupted in osm-5 mutant worms. Development 128: 1493-1505, 2001.
    • (2001) Development , vol.128 , pp. 1493-1505
    • Haycraft, C.J.1    Swoboda, P.2    Taulman, P.D.3    Thomas, J.H.4    Yoder, B.K.5
  • 31
    • 0036707893 scopus 로고    scopus 로고
    • Genetics and pathogenesis of polycystic kidney disease
    • Igarashi P and Somlo S. Genetics and pathogenesis of polycystic kidney disease. J Am Soc Nephrol 13: 2384-2398, 2002.
    • (2002) J Am Soc Nephrol , vol.13 , pp. 2384-2398
    • Igarashi, P.1    Somlo, S.2
  • 33
    • 0035475115 scopus 로고    scopus 로고
    • Exploring the molecular basis of Bardet-Biedl syndrome
    • Katsanis N, Lupski JR, and Beales PL. Exploring the molecular basis of Bardet-Biedl syndrome. Hum Mol Genet 10: 2293-2299, 2001.
    • (2001) Hum Mol Genet , vol.10 , pp. 2293-2299
    • Katsanis, N.1    Lupski, J.R.2    Beales, P.L.3
  • 35
    • 0035171012 scopus 로고    scopus 로고
    • The pck rat: A new model that resembles human autosomal dominant polycystic kidney and liver disease
    • Lager DJ, Qian Q, Bengal RJ, Ishibashi M, and Torres VE. The pck rat: a new model that resembles human autosomal dominant polycystic kidney and liver disease. Kidney Int 59: 126-136, 2001.
    • (2001) Kidney Int , vol.59 , pp. 126-136
    • Lager, D.J.1    Qian, Q.2    Bengal, R.J.3    Ishibashi, M.4    Torres, V.E.5
  • 37
    • 0037884961 scopus 로고    scopus 로고
    • Kidneyspecific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease
    • Lin F, Hiesberger T, Cordes K, Sinclair AM, Goldstein LS, Somlo S, and Igarashi P. Kidneyspecific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci USA 100: 5286-5291, 2003.
    • (2003) Proc Natl Acad Sci USA , vol.100 , pp. 5286-5291
    • Lin, F.1    Hiesberger, T.2    Cordes, K.3    Sinclair, A.M.4    Goldstein, L.S.5    Somlo, S.6    Igarashi, P.7
  • 39
    • 0015030432 scopus 로고
    • An inherited kidney disease of mice resembling human nephronophthisis
    • Lyon MF and Hulse EV. An inherited kidney disease of mice resembling human nephronophthisis. J Med Genet 8: 41-48, 1971.
    • (1971) J Med Genet , vol.8 , pp. 41-48
    • Lyon, M.F.1    Hulse, E.V.2
  • 40
    • 0028869162 scopus 로고
    • Polycystic kidney disease: Etiology, pathogenesis, and treatment
    • Martinez JR and Grantham JJ. Polycystic kidney disease: etiology, pathogenesis, and treatment. Dis Mon 41: 693-765, 1995.
    • (1995) Dis Mon , vol.41 , pp. 693-765
    • Martinez, J.R.1    Grantham, J.J.2
  • 41
    • 0038784537 scopus 로고    scopus 로고
    • Two populations of node monocilia initiate left-right asymmetry in the mouse
    • McGrath J, Somlo S, Makova S, Tian X, and Brueckner M. Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 114: 61-73, 2003.
    • (2003) Cell , vol.114 , pp. 61-73
    • McGrath, J.1    Somlo, S.2    Makova, S.3    Tian, X.4    Brueckner, M.5
  • 42
    • 0035369841 scopus 로고    scopus 로고
    • Mechanisms of Ca(2+)-dependent transcription
    • Mellstrom B and Naranjo JR. Mechanisms of Ca(2+)-dependent transcription. Curr Opin Neurobiol 11: 312-319, 2001.
    • (2001) Curr Opin Neurobiol , vol.11 , pp. 312-319
    • Mellstrom, B.1    Naranjo, J.R.2
  • 48
    • 0034042763 scopus 로고    scopus 로고
    • The Oak Ridge Polycystic Kidney (orpk) disease gene is required for left-right axis determination
    • Murcia NS, Richards WG, Yoder BK, Mucenski ML, Dunlap JR, and Woychik RP. The Oak Ridge Polycystic Kidney (orpk) disease gene is required for left-right axis determination. Development 127: 2347-2355, 2000.
    • (2000) Development , vol.127 , pp. 2347-2355
    • Murcia, N.S.1    Richards, W.G.2    Yoder, B.K.3    Mucenski, M.L.4    Dunlap, J.R.5    Woychik, R.P.6
  • 52
    • 0027406817 scopus 로고
    • Renal and biliary abnormalities in a new murine model of autosomal recessive polycystic kidney disease
    • Nauta J, Ozawa Y, Sweeney WE Jr, Rutledge JC, and Avner ED. Renal and biliary abnormalities in a new murine model of autosomal recessive polycystic kidney disease. Pediatr Nephrol 7: 163-172, 1993.
    • (1993) Pediatr Nephrol , vol.7 , pp. 163-172
    • Nauta, J.1    Ozawa, Y.2    Sweeney Jr., W.E.3    Rutledge, J.C.4    Avner, E.D.5
  • 53
    • 0032428685 scopus 로고    scopus 로고
    • Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein
    • Nonaka S, Tanaka Y, Okada Y, Takeda S, Harada A, Kanai Y, Kido M, and Hirokawa N. Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 95: 829-837, 1998.
    • (1998) Cell , vol.95 , pp. 829-837
    • Nonaka, S.1    Tanaka, Y.2    Okada, Y.3    Takeda, S.4    Harada, A.5    Kanai, Y.6    Kido, M.7    Hirokawa, N.8
  • 59
    • 0030480526 scopus 로고    scopus 로고
    • Characterization and cell distribution of polycystin, the product of autosomal dominant polycystic kidney disease gene 1
    • Palsson R, Sharma CP, Kim K, McLaughlin M, Brown D, and Arnaout MA. Characterization and cell distribution of polycystin, the product of autosomal dominant polycystic kidney disease gene 1. Mol Med 2: 702-711, 1996.
    • (1996) Mol Med , vol.2 , pp. 702-711
    • Palsson, R.1    Sharma, C.P.2    Kim, K.3    McLaughlin, M.4    Brown, D.5    Arnaout, M.A.6
  • 60
    • 0034735526 scopus 로고    scopus 로고
    • Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene Tg737, are required for assembly of cilia and flagella
    • Pazour GJ, Dickert BL, Vucica Y, Seeley ES, Rosenbaum JL, Witman GB, and Cole DG. Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene Tg737, are required for assembly of cilia and flagella. J Cell Biol 151: 709-718, 2000.
    • (2000) J Cell Biol , vol.151 , pp. 709-718
    • Pazour, G.J.1    Dickert, B.L.2    Vucica, Y.3    Seeley, E.S.4    Rosenbaum, J.L.5    Witman, G.B.6    Cole, D.G.7
  • 61
    • 0036901166 scopus 로고    scopus 로고
    • Intraflagellar transport and cilia-dependent diseases
    • Pazour GJ and Rosenbaum JL. Intraflagellar transport and cilia-dependent diseases. Trends Cell Biol 12: 551-555, 2002.
    • (2002) Trends Cell Biol , vol.12 , pp. 551-555
    • Pazour, G.J.1    Rosenbaum, J.L.2
  • 62
    • 0037019017 scopus 로고    scopus 로고
    • Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease
    • Pazour GJ, San Agustin JT, Follit JA, Rosenbaum JL, and Witman GB. Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease. Curr Biol 12: R378-R380, 2002.
    • (2002) Curr Biol , vol.12
    • Pazour, G.J.1    San Agustin, J.T.2    Follit, J.A.3    Rosenbaum, J.L.4    Witman, G.B.5
  • 64
  • 65
    • 0035498717 scopus 로고    scopus 로고
    • Bending the MDCK cell primary cilium increases intracellular calcium
    • Praetorius HA and Spring KR. Bending the MDCK cell primary cilium increases intracellular calcium. J Membr Biol 184: 71-79, 2001.
    • (2001) J Membr Biol , vol.184 , pp. 71-79
    • Praetorius, H.A.1    Spring, K.R.2
  • 66
    • 0037557518 scopus 로고    scopus 로고
    • Removal of the MDCK cell primary cilium abolishes flow sensing
    • Praetorius HA and Spring KR. Removal of the MDCK cell primary cilium abolishes flow sensing. J Membr Biol 191: 69-76, 2003.
    • (2003) J Membr Biol , vol.191 , pp. 69-76
    • Praetorius, H.A.1    Spring, K.R.2
  • 67
    • 0020048608 scopus 로고
    • Murine congenital polycystic kidney disease: A model for studying development of cystic disease
    • Preminger GM, Koch WE, Fried FA, McFarland E, Murphy ED, and Mandell J. Murine congenital polycystic kidney disease: a model for studying development of cystic disease. J Urol 127: 556-560, 1982.
    • (1982) J Urol , vol.127 , pp. 556-560
    • Preminger, G.M.1    Koch, W.E.2    Fried, F.A.3    McFarland, E.4    Murphy, E.D.5    Mandell, J.6
  • 69
    • 0016802455 scopus 로고
    • The sensory cilium of retinal rods is analogous to the transitional zone of motile cilia
    • Rohlich P. The sensory cilium of retinal rods is analogous to the transitional zone of motile cilia. Cell Tissue Res 161: 421-430, 1975.
    • (1975) Cell Tissue Res , vol.161 , pp. 421-430
    • Rohlich, P.1
  • 71
    • 0032241832 scopus 로고    scopus 로고
    • Molecular analysis of neurotransmitter release
    • Schiavo G and Stenbeck G. Molecular analysis of neurotransmitter release. Essays Biochem 33: 29-41, 1998.
    • (1998) Essays Biochem , vol.33 , pp. 29-41
    • Schiavo, G.1    Stenbeck, G.2
  • 72
    • 0038141062 scopus 로고    scopus 로고
    • Towards the identification of (a) gene(s) for autosomal dominant medullary cystic kidney disease
    • Scolari F, Viola BF, Ghiggeri GM, Caridi G, Amoroso A, Rampoldi L, and Casari G. Towards the identification of (a) gene(s) for autosomal dominant medullary cystic kidney disease. J Nephrol 16: 321-328, 2003.
    • (2003) J Nephrol , vol.16 , pp. 321-328
    • Scolari, F.1    Viola, B.F.2    Ghiggeri, G.M.3    Caridi, G.4    Amoroso, A.5    Rampoldi, L.6    Casari, G.7
  • 73
    • 0035951789 scopus 로고    scopus 로고
    • 2+-dependent cell signaling through calmodulin-activated protein phosphatase and protein kinases minireview series
    • 2+-dependent cell signaling through calmodulin-activated protein phosphatase and protein kinases minireview series. J Biol Chem 276: 2311-2312, 2001.
    • (2001) J Biol Chem , vol.276 , pp. 2311-2312
    • Stull, J.T.1
  • 76
    • 0035159015 scopus 로고    scopus 로고
    • Polaris, a protein involved in left-right axis patterning, localizes to basal bodies and cilia
    • Taulman PD, Haycraft CJ, Balkovetz DF, and Yoder BK. Polaris, a protein involved in left-right axis patterning, localizes to basal bodies and cilia. Mol Biol Cell 12: 589-599, 2001.
    • (2001) Mol Biol Cell , vol.12 , pp. 589-599
    • Taulman, P.D.1    Haycraft, C.J.2    Balkovetz, D.F.3    Yoder, B.K.4
  • 79
    • 0037959910 scopus 로고    scopus 로고
    • The left-right determinant Inversin is a component of node monocilia and other 9+0 cilia
    • Watanabe D, Saijoh Y, Nonaka S, Sasaki G, Ikawa Y, Yokoyama T, and Hamada H. The left-right determinant Inversin is a component of node monocilia and other 9+0 cilia. Development 130: 1725-1734, 2003.
    • (2003) Development , vol.130 , pp. 1725-1734
    • Watanabe, D.1    Saijoh, Y.2    Nonaka, S.3    Sasaki, G.4    Ikawa, Y.5    Yokoyama, T.6    Hamada, H.7
  • 81
    • 0029035757 scopus 로고
    • Apoptosis and loss of renal tissue in polycystic kidney diseases
    • Woo D. Apoptosis and loss of renal tissue in polycystic kidney diseases. N Engl J Med 333: 18-25, 1995.
    • (1995) N Engl J Med , vol.333 , pp. 18-25
    • Woo, D.1
  • 83
    • 0031260133 scopus 로고    scopus 로고
    • Molecular cloning, cdna sequence analysis, and chromosomal localization of mouse Pkd2
    • Wu GQ, Mochizuki T, Le TC, Cai YQ, Hayashi T, Reynolds DM, and Somlo S. Molecular cloning, cdna sequence analysis, and chromosomal localization of mouse Pkd2. Genomics 45: 220-223, 1997.
    • (1997) Genomics , vol.45 , pp. 220-223
    • Wu, G.Q.1    Mochizuki, T.2    Le, T.C.3    Cai, Y.Q.4    Hayashi, T.5    Reynolds, D.M.6    Somlo, S.7
  • 84
    • 0036785149 scopus 로고    scopus 로고
    • The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia
    • Yoder BK, Hou X, and Guay-Woodford LM. The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol 13: 2508-2516, 2002.
    • (2002) J Am Soc Nephrol , vol.13 , pp. 2508-2516
    • Yoder, B.K.1    Hou, X.2    Guay-Woodford, L.M.3


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.