{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T22:22:01Z","timestamp":1778019721094,"version":"3.51.4"},"reference-count":43,"publisher":"The Company of Biologists","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,5,15]]},"abstract":"<jats:p>Different mutations of \u03b13 connexin (Cx46 or Gja8) and\u03b18 connexin (Cx50 or Gja8), subunits of lens gap junction channels, cause a variety of cataracts via unknown mechanisms. We identified a dominant cataractous mouse line (L1), caused by a missense \u03b18 connexin mutation that resulted in the expression of \u03b18-S50P mutant proteins. Histology studies showed that primary lens fiber cells failed to fully elongate in heterozygous \u03b18S50P\/+ embryonic lenses, but not in homozygous \u03b18S50P\/S50P, \u03b18-\/- and\u03b13-\/- \u03b18-\/- mutant embryonic lenses. We hypothesized that \u03b18-S50P mutant subunits interacted with wild-type\u03b13 or \u03b18, or with both subunits to affect fiber cell formation. We found that the combination of mutant \u03b18-S50P and wild-type \u03b18 subunits specifically inhibited the elongation of primary fiber cells, while the combination of \u03b18-S50P and wild-type \u03b13 subunits disrupted the formation of secondary fiber cells. Thus, this work provides the first in vivo evidence that distinct mechanisms, modulated by diverse gap junctions, control the formation of primary and secondary fiber cells during lens development. This explains why and how different connexin mutations lead to a variety of cataracts. The principle of this explanation can also be applied to mutations of other connexin isoforms that cause different diseases in other organs.<\/jats:p>","DOI":"10.1242\/dev.02361","type":"journal-article","created":{"date-parts":[[2006,4,13]],"date-time":"2006-04-13T00:26:37Z","timestamp":1144887997000},"page":"2033-2040","source":"Crossref","is-referenced-by-count":35,"title":["Diverse gap junctions modulate distinct mechanisms for fiber cell formation during lens development and cataractogenesis"],"prefix":"10.1242","volume":"133","author":[{"given":"Chun-hong","family":"Xia","sequence":"first","affiliation":[{"name":"School of Optometry and Vision Science Program, University of California at Berkeley, Berkeley, CA 94720, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiquan","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Optometry and Vision Science Program, University of California at Berkeley, Berkeley, CA 94720, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debra","family":"Cheung","sequence":"additional","affiliation":[{"name":"School of Optometry and Vision Science Program, University of California at Berkeley, Berkeley, CA 94720, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Cheng","sequence":"additional","affiliation":[{"name":"UC Berkeley\/UCSF Joint Bioengineering Graduate Program, University of California at Berkeley, Berkeley, CA 94720, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eddie","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Optometry and Vision Science Program, University of California at Berkeley, Berkeley, CA 94720, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037,USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce","family":"Beutler","sequence":"additional","affiliation":[{"name":"Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037,USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Woo-Kuen","family":"Lo","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurobiology, Morehouse School of Medicine, Atlanta,GA 30310, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohua","family":"Gong","sequence":"additional","affiliation":[{"name":"School of Optometry and Vision Science Program, University of California at Berkeley, Berkeley, CA 94720, USA."},{"name":"UC Berkeley\/UCSF Joint Bioengineering Graduate Program, University of California at Berkeley, Berkeley, CA 94720, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","reference":[{"key":"2021042601071437500_REF1","doi-asserted-by":"crossref","unstructured":"Bassnett, S. (2004). Lens fiber differentiation. In Development of the Ocular Lens(ed. F. J. Lovicu and M. L. Robinson), pp. 214-244. Cambridge: Cambridge University Press.","DOI":"10.1017\/CBO9780511529825.010"},{"key":"2021042601071437500_REF2","doi-asserted-by":"crossref","unstructured":"Bassnett, S. (2005). Three-dimensional reconstruction of cells in the living lens: the relationship between cell length and volume. Exp. Eye Res.81,716-723.","DOI":"10.1016\/j.exer.2005.04.009"},{"key":"2021042601071437500_REF3","doi-asserted-by":"crossref","unstructured":"Beebe, D. C., Compart, P. J., Johnson, M. C., Feagans, D. E. and Feinberg, R. N. (1982). The mechanism of cell elongation during lens fiber cell differentiation. Dev. Biol.92, 54-59.","DOI":"10.1016\/0012-1606(82)90149-X"},{"key":"2021042601071437500_REF4","unstructured":"Bennett, T. M., Mackay, D. S., Knopf, H. L. and Shiels, A.(2004). A novel missense mutation in the gene for gap-junction protein alpha3 (GJA3) associated with autosomal dominant \u201cnuclear punctate\u201d cataracts linked to chromosome 13q. Mol. Vis.10,376-382."},{"key":"2021042601071437500_REF5","doi-asserted-by":"crossref","unstructured":"Berry, V., Mackay, D., Khaliq, S., Francis, P. J., Hameed, A.,Anwar, K., Mehdi, S. Q., Newbold, R. J., Ionides, A., Shiels, A. et al.(1999). Connexin 50 mutation in a family with congenital\u201czonular nuclear\u201d pulverulent cataract of Pakistani origin. Hum. Genet.105,168-170.","DOI":"10.1007\/s004399900094"},{"key":"2021042601071437500_REF6","doi-asserted-by":"crossref","unstructured":"Berthoud, V. M., Minogue, P. J., Guo, J., Williamson, E. K., Xu,X., Ebihara, L. and Beyer, E. C. (2003). Loss of function and impaired degradation of a cataract-associated mutant connexin50. Eur. J. Cell Biol.82,209-221.","DOI":"10.1078\/0171-9335-00316"},{"key":"2021042601071437500_REF7","doi-asserted-by":"crossref","unstructured":"Chang, B., Wang, X., Hawes, N. L., Ojakian, R., Davisson, M. T.,Lo, W. K. and Gong, X. (2002). A Gja8 (Cx50) point mutation causes an alteration of alpha 3 connexin (Cx46) in semi-dominant cataracts of Lop10 mice. Hum. Mol. Genet.11,507-513.","DOI":"10.1093\/hmg\/11.5.507"},{"key":"2021042601071437500_REF8","doi-asserted-by":"crossref","unstructured":"Du, X., Tabeta, K., Hoebe, K., Liu, H., Mann, N., Mudd, S.,Crozat, K., Sovath, S., Gong, X. and Beutler, B. (2004). Velvet, a dominant Egfr mutation that causes wavy hair and defective eyelid development in mice. Genetics166,331-340.","DOI":"10.1534\/genetics.166.1.331"},{"key":"2021042601071437500_REF9","doi-asserted-by":"crossref","unstructured":"Fleishman, S. J., Unger, V. M., Yeager, M. and Ben-Tal, N.(2004). A Calpha model for the transmembrane alpha helices of gap junction intercellular channels. Mol. Cell15,879-888.","DOI":"10.1016\/j.molcel.2004.08.016"},{"key":"2021042601071437500_REF10","doi-asserted-by":"crossref","unstructured":"Flenniken, A. M., Osborne, L. R., Anderson, N., Ciliberti, N.,Fleming, C., Gittens, J. E., Gong, X. Q., Kelsey, L. B., Lounsbury, C.,Moreno, L. et al. (2005). A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia. Development132,4375-4386.","DOI":"10.1242\/dev.02011"},{"key":"2021042601071437500_REF11","doi-asserted-by":"crossref","unstructured":"Gong, X., Li, E., Klier, G., Huang, Q., Wu, Y., Lei, H., Kumar,N. M., Horwitz, J. and Gilula, N. B. (1997). Disruption of alpha3 connexin gene leads to proteolysis and cataractogenesis in mice. Cell91,833-843.","DOI":"10.1016\/S0092-8674(00)80471-7"},{"key":"2021042601071437500_REF12","unstructured":"Goodenough, D. A. (1992). The crystalline lens. A system networked by gap junctional intercellular communication. Semin. Cell Biol.3,49-58."},{"key":"2021042601071437500_REF13","doi-asserted-by":"crossref","unstructured":"Goodenough, D. A., Goliger, J. A. and Paul, D. L.(1996). Connexins, connexons, and intercellular communication. Annu. Rev. Biochem.65,475-502.","DOI":"10.1146\/annurev.bi.65.070196.002355"},{"key":"2021042601071437500_REF14","doi-asserted-by":"crossref","unstructured":"Graw, J., Loster, J., Soewarto, D., Fuchs, H., Meyer, B., Reis,A., Wolf, E., Balling, R. and Hrabe de Angelis, M. (2001). Characterization of a mutation in the lens-specific MP70 encoding gene of the mouse leading to a dominant cataract. Exp. Eye Res.73,867-876.","DOI":"10.1006\/exer.2001.1096"},{"key":"2021042601071437500_REF15","doi-asserted-by":"crossref","unstructured":"Hopperstad, M. G., Srinivas, M. and Spray, D. C.(2000). Properties of gap junction channels formed by Cx46 alone and in combination with Cx50. Biophys. J.79,1954-1966.","DOI":"10.1016\/S0006-3495(00)76444-7"},{"key":"2021042601071437500_REF16","unstructured":"Jiang, H., Jin, Y., Bu, L., Zhang, W., Liu, J., Cui, B., Kong,X. and Hu, L. (2003). A novel mutation in GJA3 (connexin46)for autosomal dominant congenital nuclear pulverulent cataract. Mol. Vis.9,579-583."},{"key":"2021042601071437500_REF17","doi-asserted-by":"crossref","unstructured":"Jiang, J. X. and Goodenough, D. A. (1996). Heteromeric connexons in lens gap junction channels. Proc. Natl. Acad. Sci. USA93,1287-1291.","DOI":"10.1073\/pnas.93.3.1287"},{"key":"2021042601071437500_REF18","doi-asserted-by":"crossref","unstructured":"Kim, J. I., Li, T., Ho, I. C., Grusby, M. J. and Glimcher, L. H. (1999). Requirement for the c-Maf transcription factor in crystallin gene regulation and lens development. Proc. Natl. Acad. Sci. USA96,3781-3785.","DOI":"10.1073\/pnas.96.7.3781"},{"key":"2021042601071437500_REF19","doi-asserted-by":"crossref","unstructured":"Konig, N. and Zampighi, G. A. (1995). Purification of bovine lens cell-to-cell channels composed of connexin44 and connexin50. J. Cell Sci.108,3091-3098.","DOI":"10.1242\/jcs.108.9.3091"},{"key":"2021042601071437500_REF20","doi-asserted-by":"crossref","unstructured":"Kumar, N. M. and Gilula, N. B. (1996). The gap junction communication channel. Cell84,381-388.","DOI":"10.1016\/S0092-8674(00)81282-9"},{"key":"2021042601071437500_REF21","doi-asserted-by":"crossref","unstructured":"Kuszak, J. R., Zoltoski, R. K. and Sivertson, C.(2004). Fibre cell organization in crystalline lenses. Exp. Eye Res.78,673-687.","DOI":"10.1016\/j.exer.2003.09.016"},{"key":"2021042601071437500_REF22","unstructured":"Li, Y., Wang, J., Dong, B. and Man, H. (2004). A novel connexin46 (GJA3) mutation in autosomal dominant congenital nuclear pulverulent cataract. Mol. Vis.10,668-671."},{"key":"2021042601071437500_REF23","doi-asserted-by":"crossref","unstructured":"Lo, W. K., Shaw, A. P., Takemoto, L. J., Grossniklaus, H. E. and Tigges, M. (1996). Gap junction structures and distribution patterns of immunoreactive connexins 46 and 50 in lens regrowths of Rhesus monkeys. Exp. Eye Res.62,171-180.","DOI":"10.1006\/exer.1996.0021"},{"key":"2021042601071437500_REF24","doi-asserted-by":"crossref","unstructured":"Mackay, D., Ionides, A., Kibar, Z., Rouleau, G., Berry, V.,Moore, A., Shiels, A. and Bhattacharya, S. (1999). Connexin46 mutations in autosomal dominant congenital cataract. Am. J. Hum. Genet.64,1357-1364.","DOI":"10.1086\/302383"},{"key":"2021042601071437500_REF25","doi-asserted-by":"crossref","unstructured":"Martinez-Wittinghan, F. J., Sellitto, C., Li, L., Gong, X.,Brink, P. R., Mathias, R. T. and White, T. W. (2003). Dominant cataracts result from incongruous mixing of wild-type lens connexins. J. Cell Biol.161,969-978.","DOI":"10.1083\/jcb.200303068"},{"key":"2021042601071437500_REF26","doi-asserted-by":"crossref","unstructured":"Martinez-Wittinghan, F. J., Sellitto, C., White, T. W., Mathias,R. T., Paul, D. and Goodenough, D. A. (2004). Lens gap junctional coupling is modulated by connexin identity and the locus of gene expression. Invest. Ophthalmol. Vis. Sci.45,3629-3637.","DOI":"10.1167\/iovs.04-0445"},{"key":"2021042601071437500_REF27","doi-asserted-by":"crossref","unstructured":"Mathias, R. T., Rae, J. L. and Baldo, G. J.(1997). Physiological properties of the normal lens. Physiol. Rev.77,21-50.","DOI":"10.1152\/physrev.1997.77.1.21"},{"key":"2021042601071437500_REF28","doi-asserted-by":"crossref","unstructured":"Ogino, H. and Yasuda, K. (2000). Sequential activation of transcription factors in lens induction. Dev. Growth Differ.42,437-448.","DOI":"10.1046\/j.1440-169x.2000.00532.x"},{"key":"2021042601071437500_REF29","doi-asserted-by":"crossref","unstructured":"Parmelee, J. T. and Beebe, D. C. (1988). Decreased membrane permeability to potassium is responsible for the cell volume increase that drives lens fiber cell elongation. J. Cell Physiol.134,491-496.","DOI":"10.1002\/jcp.1041340323"},{"key":"2021042601071437500_REF30","doi-asserted-by":"crossref","unstructured":"Piatigorsky, J. (1981). Lens differentiation in vertebrates. A review of cellular and molecular features. Differentiation19,134-153.","DOI":"10.1111\/j.1432-0436.1981.tb01141.x"},{"key":"2021042601071437500_REF31","doi-asserted-by":"crossref","unstructured":"Polyakov, A. V., Shagina, I. A., Khlebnikova, O. V. and Evgrafov, O. V. (2001). Mutation in the connexin 50 gene(GJA8) in a Russian family with zonular pulverulent cataract. Clin. Genet.60,476-478.","DOI":"10.1034\/j.1399-0004.2001.600614.x"},{"key":"2021042601071437500_REF32","unstructured":"Rees, M. I., Watts, P., Fenton, I., Clarke, A., Snell, R. G.,Owen, M. J. and Gray, J. (2000). Further evidence of autosomal dominant congenital zonular pulverulent cataracts linked to 13q11(CZP3) and a novel mutation in connexin 46 (GJA3). Hum. Genet.106,206-209."},{"key":"2021042601071437500_REF33","unstructured":"Rong, P., Wang, X., Niesman, I., Wu, Y., Benedetti, L. E.,Dunia, I., Levy, E. and Gong, X. (2002). Disruption of Gja8(alpha8 connexin) in mice leads to microphthalmia associated with retardation of lens growth and lens fiber maturation. Development129,167-174."},{"key":"2021042601071437500_REF34","doi-asserted-by":"crossref","unstructured":"Sellitto, C., Li, L. and White, T. W. (2004). Connexin50 is essential for normal postnatal lens cell proliferation. Invest. Ophthalmol. Vis. Sci.45,3196-3202.","DOI":"10.1167\/iovs.04-0194"},{"key":"2021042601071437500_REF35","doi-asserted-by":"crossref","unstructured":"Shiels, A., Mackay, D., Ionides, A., Berry, V., Moore, A. and Bhattacharya, S. (1998). A missense mutation in the human connexin50 gene (GJA8) underlies autosomal dominant \u201czonular pulverulent\u201d cataract, on chromosome 1q. Am. J. Hum. Genet.62,526-532.","DOI":"10.1086\/301762"},{"key":"2021042601071437500_REF36","doi-asserted-by":"crossref","unstructured":"Steele, E. C., Jr, Lyon, M. F., Favor, J., Guillot, P. V., Boyd,Y. and Church, R. L. (1998). A mutation in the connexin 50(Cx50) gene is a candidate for the No2 mouse cataract. Curr. Eye Res.17,883-889.","DOI":"10.1076\/ceyr.17.9.883.5144"},{"key":"2021042601071437500_REF37","doi-asserted-by":"crossref","unstructured":"Unger, V. M., Kumar, N. M., Gilula, N. B. and Yeager, M.(1999). Three-dimensional structure of a recombinant gap junction membrane channel. Science283,1176-1180.","DOI":"10.1126\/science.283.5405.1176"},{"key":"2021042601071437500_REF38","doi-asserted-by":"crossref","unstructured":"White, T. W., Bruzzone, R., Wolfram, S., Paul, D. L. and Goodenough, D. A. (1994). Selective interactions among the multiple connexin proteins expressed in the vertebrate lens: the second extracellular domain is a determinant of compatibility between connexins. J. Cell Biol.125,879-892.","DOI":"10.1083\/jcb.125.4.879"},{"key":"2021042601071437500_REF39","doi-asserted-by":"crossref","unstructured":"White, T. W., Goodenough, D. A. and Paul, D. L.(1998). Targeted ablation of connexin50 in mice results in microphthalmia and zonular pulverulent cataracts. J. Cell Biol.143,815-825.","DOI":"10.1083\/jcb.143.3.815"},{"key":"2021042601071437500_REF40","doi-asserted-by":"crossref","unstructured":"Wigle, J. T., Chowdhury, K., Gruss, P. and Oliver, G.(1999). Prox1 function is crucial for mouse lens-fibre elongation. Nat. Genet.21,318-322.","DOI":"10.1038\/6844"},{"key":"2021042601071437500_REF41","doi-asserted-by":"crossref","unstructured":"Willoughby, C. E., Arab, S., Gandhi, R., Zeinali, S., Luk, D.,Billingsley, G., Munier, F. L. and Heon, E. (2003). A novel GJA8 mutation in an Iranian family with progressive autosomal dominant congenital nuclear cataract. J. Med. Genet.40, e124.","DOI":"10.1136\/jmg.40.11.e124"},{"key":"2021042601071437500_REF42","doi-asserted-by":"crossref","unstructured":"Yeager, M. and Nicholson, B. J. (2000). Structure and biochemistry of gap junction. Adv. Mol. Cell Biol.30,31-98.","DOI":"10.1016\/S1569-2558(00)30003-0"},{"key":"2021042601071437500_REF43","unstructured":"Zheng, J. Q., Ma, Z. W. and Sun, H. M. (2005).[A heterozygous transversion of connexin 50 in a family with congenital nuclear cataract in the northeast of China]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi22,76-78."}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/133\/10\/2033\/1470127\/2033.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/133\/10\/2033\/1470127\/2033.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T01:08:00Z","timestamp":1619399280000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/133\/10\/2033\/37566\/Diverse-gap-junctions-modulate-distinct-mechanisms"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,5,15]]},"references-count":43,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2006,5,15]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.02361","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2006,5,15]]}}}