© The Rockefeller University Press,
0021-9525/1998//815 $5.00
The Journal of Cell Biology, Volume 143, Number 3,
, 1998 815-825
Targeted Ablation of Connexin50 in Mice Results in Microphthalmia and Zonular Pulverulent Cataracts
Thomas W. White,
Daniel A. Goodenough, and
David L. Paul
Department of Cell Biology and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115
In the ocular lens, gap junctional communication is a key component of homeostatic mechanisms preventing cataract formation. Gap junctions in rodent lens fibers contain two known intercellular channel-forming proteins, connexin50 (Cx50) and Cx46. Since targeted ablation of Cx46 has been shown to cause senile-type nuclear opacities, it appears that Cx50 alone cannot meet homeostatic requirements. To determine if lens pathology arises from a reduction in levels of communication or the loss of a connexin-specific function, we have generated mice with a targeted deletion of the Cx50 gene. Cx50-null mice exhibited microphthalmia and nuclear cataracts. At postnatal day 14 (P14), Cx50-knockout eyes weighed 32% less than controls, whereas lens mass was reduced by 46%. Cx50-knockout lenses also developed zonular pulverulent cataracts, and lens abnormalities were detected by P7. Deletion of Cx50 did not alter the amounts or distributions of Cx46 or Cx43, a component of lens epithelial junctions. In addition, intercellular passage of tracers revealed the persistence of communication between all cell types in the Cx50-knockout lens. These results demonstrate that Cx50 is required not only for maintenance of lens transparency but also for normal eye growth. Furthermore, these data indicate that unique functional properties of both Cx46 and Cx50 are required for proper lens development.
Key Words: lens gap junction connexin microphthalmia cataract
Abbreviations used in this paper: Cx, connexin; Cx50, connexin50; E, embryonic day; P, postnatal day.

CiteULike
Complore
Connotea
Del.icio.us
Digg
Facebook
Reddit
Technorati
Twitter What's this?
This article has been cited by other articles:
-
Goodenough, D. A., Paul, D. L.
(2009). Gap Junctions. Cold Spring Harb. Perspect. Biol.
1: a002576-a002576
[Abstract]
[Full Text]
-
Ponnam, S. P. G, Ramesha, K., Tejwani, S., Ramamurthy, B., Kannabiran, C.
(2009). Mutation of the gap junction protein alpha 8 (GJA8) gene causes autosomal recessive cataract. BMJ Case Reports
2009: bcr0620091995-bcr0620091995
[Abstract]
[Full Text]
-
Retamal, M. A., Yin, S., Altenberg, G. A., Reuss, L.
(2009). Modulation of Cx46 hemichannels by nitric oxide. Am. J. Physiol. Cell Physiol.
296: C1356-C1363
[Abstract]
[Full Text]
-
Das, S., Smith, T. D., Sarma, J. D., Ritzenthaler, J. D., Maza, J., Kaplan, B. E., Cunningham, L. A., Suaud, L., Hubbard, M. J., Rubenstein, R. C., Koval, M.
(2009). ERp29 Restricts Connexin43 Oligomerization in the Endoplasmic Reticulum. Mol. Biol. Cell
20: 2593-2604
[Abstract]
[Full Text]
-
Shakespeare, T. I., Sellitto, C., Li, L., Rubinos, C., Gong, X., Srinivas, M., White, T. W.
(2009). Interaction between Connexin50 and Mitogen-activated Protein Kinase Signaling in Lens Homeostasis. Mol. Biol. Cell
20: 2582-2592
[Abstract]
[Full Text]
-
Banks, E. A., Toloue, M. M., Shi, Q., Zhou, Z. J., Liu, J., Nicholson, B. J., Jiang, J. X.
(2009). Connexin mutation that causes dominant congenital cataracts inhibits gap junctions, but not hemichannels, in a dominant negative manner. J. Cell Sci.
122: 378-388
[Abstract]
[Full Text]
-
Cooper, M. A., Son, A. I., Komlos, D., Sun, Y., Kleiman, N. J., Zhou, R.
(2008). Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract. Proc. Natl. Acad. Sci. USA
105: 16620-16625
[Abstract]
[Full Text]
-
Thomas, B. C., Minogue, P. J., Valiunas, V., Kanaporis, G., Brink, P. R., Berthoud, V. M., Beyer, E. C.
(2008). Cataracts Are Caused by Alterations of a Critical N-Terminal Positive Charge in Connexin50. IOVS
49: 2549-2556
[Abstract]
[Full Text]
-
Boswell, B. A., Lein, P. J., Musil, L. S.
(2008). Cross-Talk between Fibroblast Growth Factor and Bone Morphogenetic Proteins Regulates Gap Junction-mediated Intercellular Communication in Lens Cells. Mol. Biol. Cell
19: 2631-2641
[Abstract]
[Full Text]
-
Shearer, D., Ens, W., Standing, K., Valdimarsson, G.
(2008). Posttranslational Modifications in Lens Fiber Connexins Identified by Off-Line-HPLC MALDI-Quadrupole Time-of-Flight Mass Spectrometry. IOVS
49: 1553-1562
[Abstract]
[Full Text]
-
Arora, A, Minogue, P J, Liu, X, Addison, P K, Russel-Eggitt, I, Webster, A R, Hunt, D M, Ebihara, L, Beyer, E C, Berthoud, V M, Moore, A T
(2008). A novel connexin50 mutation associated with congenital nuclear pulverulent cataracts. J. Med. Genet.
45: 155-160
[Abstract]
[Full Text]
-
White, T. W., Gao, Y., Li, L., Sellitto, C., Srinivas, M.
(2007). Optimal Lens Epithelial Cell Proliferation Is Dependent on the Connexin Isoform Providing Gap Junctional Coupling. IOVS
48: 5630-5637
[Abstract]
[Full Text]
-
Lurtz, M. M., Louis, C. F.
(2007). Intracellular calcium regulation of connexin43. Am. J. Physiol. Cell Physiol.
293: C1806-C1813
[Abstract]
[Full Text]
-
Banks, E. A., Yu, X. S., Shi, Q., Jiang, J. X.
(2007). Promotion of lens epithelial-fiber differentiation by the C-terminus of connexin 45.6 a role independent of gap junction communication. J. Cell Sci.
120: 3602-3612
[Abstract]
[Full Text]
-
Ponnam, S. P. G, Ramesha, K., Tejwani, S., Ramamurthy, B., Kannabiran, C.
(2007). Mutation of the gap junction protein alpha 8 (GJA8) gene causes autosomal recessive cataract. J. Med. Genet.
44: e85-e85
[Abstract]
[Full Text]
-
O'Brien, J. J., Li, W., Pan, F., Keung, J., O'Brien, J., Massey, S. C.
(2006). Coupling between A-Type Horizontal Cells Is Mediated by Connexin 50 Gap Junctions in the Rabbit Retina.. J. Neurosci.
26: 11624-11636
[Abstract]
[Full Text]
-
Lin, D., Barnett, M., Lobell, S., Madgwick, D., Shanks, D., Willard, L., Zampighi, G. A., Takemoto, D. J.
(2006). PKC{gamma} knockout mouse lenses are more susceptible to oxidative stress damage. J. Exp. Biol.
209: 4371-4378
[Abstract]
[Full Text]
-
Calera, M. R., Topley, H. L., Liao, Y., Duling, B. R., Paul, D. L., Goodenough, D. A.
(2006). Connexin43 is required for production of the aqueous humor in the murine eye. J. Cell Sci.
119: 4510-4519
[Abstract]
[Full Text]
-
Xia, C.-h., Cheung, D., DeRosa, A. M., Chang, B., Lo, W.-K., White, T. W., Gong, X.
(2006). Knock-in of {alpha}3 connexin prevents severe cataracts caused by an {alpha}8 point mutation. J. Cell Sci.
119: 2138-2144
[Abstract]
[Full Text]
-
Xia, C.-h., Liu, H., Cheung, D., Cheng, C., Wang, E., Du, X., Beutler, B., Lo, W.-K., Gong, X.
(2006). Diverse gap junctions modulate distinct mechanisms for fiber cell formation during lens development and cataractogenesis. Development
133: 2033-2040
[Abstract]
[Full Text]
-
Arora, A, Minogue, P J, Liu, X, Reddy, M A, Ainsworth, J R, Bhattacharya, S S, Webster, A R, Hunt, D M, Ebihara, L, Moore, A T, Beyer, E C, Berthoud, V M
(2006). A novel GJA8 mutation is associated with autosomal dominant lamellar pulverulent cataract: further evidence for gap junction dysfunction in human cataract. J. Med. Genet.
43: e2-e2
[Abstract]
[Full Text]
-
Zampighi, G. A., Planells, A. M., Lin, D., Takemoto, D.
(2005). Regulation of Lens Cell-to-Cell Communication by Activation of PKC{gamma} and Disassembly of Cx50 Channels. IOVS
46: 3247-3255
[Abstract]
[Full Text]
-
Yu, X. S., Yin, X., Lafer, E. M., Jiang, J. X.
(2005). Developmental Regulation of the Direct Interaction between the Intracellular Loop of Connexin 45.6 and the C Terminus of Major Intrinsic Protein (Aquaporin-0). J. Biol. Chem.
280: 22081-22090
[Abstract]
[Full Text]
-
Houghton, F. D
(2005). Role of gap junctions during early embryo development. Reproduction
129: 129-135
[Abstract]
[Full Text]
-
Martinez-Wittinghan, F. J., Sellitto, C., White, T. W., Mathias, R. T., Paul, D., Goodenough, D. A.
(2004). Lens Gap Junctional Coupling Is Modulated by Connexin Identity and the Locus of Gene Expression. IOVS
45: 3629-3637
[Abstract]
[Full Text]
-
Gao, J., Sun, X., Martinez-Wittinghan, F. J., Gong, X., White, T. W., Mathias, R. T.
(2004). Connections Between Connexins, Calcium, and Cataracts in the Lens. JGP
124: 289-300
[Abstract]
[Full Text]
-
Sellitto, C., Li, L., White, T. W.
(2004). Connexin50 Is Essential for Normal Postnatal Lens Cell Proliferation. IOVS
45: 3196-3202
[Abstract]
[Full Text]
-
Cheng, S., Shakespeare, T., Mui, R., White, T. W., Valdimarsson, G.
(2004). Connexin 48.5 Is Required for Normal Cardiovascular Function and Lens Development in Zebrafish Embryos. J. Biol. Chem.
279: 36993-37003
[Abstract]
[Full Text]
-
Cruikshank, S. J., Hopperstad, M., Younger, M., Connors, B. W., Spray, D. C., Srinivas, M.
(2004). Potent block of Cx36 and Cx50 gap junction channels by mefloquine. Proc. Natl. Acad. Sci. USA
101: 12364-12369
[Abstract]
[Full Text]
-
Jacobs, M. D., Soeller, C., Sisley, A. M. G., Cannell, M. B., Donaldson, P. J.
(2004). Gap Junction Processing and Redistribution Revealed by Quantitative Optical Measurements of Connexin46 Epitopes in the Lens. IOVS
45: 191-199
[Abstract]
[Full Text]
-
Lurtz, M. M., Louis, C. F.
(2003). Calmodulin and protein kinase C regulate gap junctional coupling in lens epithelial cells. Am. J. Physiol. Cell Physiol.
285: C1475-C1482
[Abstract]
[Full Text]
-
Willoughby, C E, Arab, S., Gandhi, R, Zeinali, S, Arab, S., Luk, D, Billingsley, G, Munier, F L, Heon, E
(2003). A novel GJA8 mutation in an Iranian family with progressive autosomal dominant congenital nuclear cataract. J. Med. Genet.
40: e124-124
[Full Text]
-
Shestopalov, V. I., Bassnett, S.
(2003). Development of a macromolecular diffusion pathway in the lens. J. Cell Sci.
116: 4191-4199
[Abstract]
[Full Text]
-
SAEZ, J. C., BERTHOUD, V. M., BRANES, M. C., MARTINEZ, A. D., BEYER, E. C.
(2003). Plasma Membrane Channels Formed by Connexins: Their Regulation and Functions. Physiol. Rev.
83: 1359-1400
[Abstract]
[Full Text]
-
Menichella, D. M., Goodenough, D. A., Sirkowski, E., Scherer, S. S., Paul, D. L.
(2003). Connexins Are Critical for Normal Myelination in the CNS. J. Neurosci.
23: 5963-5973
[Abstract]
[Full Text]
-
Martinez-Wittinghan, F. J., Sellitto, C., Li, L., Gong, X., Brink, P. R., Mathias, R. T., White, T. W.
(2003). Dominant cataracts result from incongruous mixing of wild-type lens connexins. JCB
161: 969-978
[Abstract]
[Full Text]
-
White, T. W.
(2003). Nonredundant Gap Junction Functions. Physiology
18: 95-99
[Abstract]
[Full Text]
-
Gerido, D. A., Sellitto, C., Li, L., White, T. W.
(2003). Genetic Background Influences Cataractogenesis, but Not Lens Growth Deficiency, in Cx50-Knockout Mice. IOVS
44: 2669-2674
[Abstract]
[Full Text]
-
Nielsen, P. A., Baruch, A., Shestopalov, V. I., Giepmans, B. N.G., Dunia, I., Benedetti, E. L., Kumar, N. M.
(2003). Lens Connexins {alpha}3Cx46 and {alpha}8Cx50 Interact with Zonula Occludens Protein-1 (ZO-1). Mol. Biol. Cell
14: 2470-2481
[Abstract]
[Full Text]
-
Gu, S., Yu, X. S., Yin, X., Jiang, J. X.
(2003). Stimulation of Lens Cell Differentiation by Gap Junction Protein Connexin 45.6. IOVS
44: 2103-2111
[Abstract]
[Full Text]
-
Koval, M.
(2002). Sharing signals: connecting lung epithelial cells with gap junction channels. Am. J. Physiol. Lung Cell. Mol. Physiol.
283: L875-L893
[Abstract]
[Full Text]
-
Yamashita, S., Furumoto, K., Nobukiyo, A., Kamohara, M., Ushijima, T., Furukawa, T.
(2002). Mapping of A Gene Responsible for Cataract Formation and Its Modifier in the UPL Rat. IOVS
43: 3153-3159
[Abstract]
[Full Text]
-
Chang, B., Wang, X., Hawes, N. L., Ojakian, R., Davisson, M. T., Lo, W.-K., 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
[Abstract]
[Full Text]
-
White, T. W.
(2002). Unique and Redundant Connexin Contributions to Lens Development. Science
295: 319-320
[Abstract]
[Full Text]
-
Rong, P., Wang, X., Niesman, I., Wu, Y., Benedetti, L. E., Dunia, I., Levy, E., Gong, X.
(2002). Disruption of Gja8 ({alpha}8 connexin) in mice leads to microphthalmia associated with retardation of lens growth and lens fiber maturation. Development
129: 167-174
[Abstract]
[Full Text]
-
White, T. W., Sellitto, C., Paul, D. L., Goodenough, D. A.
(2001). Prenatal Lens Development in Connexin43 and Connexin50 Double Knockout Mice. IOVS
42: 2916-2923
[Abstract]
[Full Text]
-
Baldo, G. J., Gong, X., Martinez-Wittinghan, F. J., Kumar, N. M., Gilula, N. B., Mathias, R. T.
(2001). Gap Junctional Coupling in Lenses from {alpha}8 Connexin Knockout Mice. JGP
118: 447-456
[Abstract]
[Full Text]
-
More, M. I., Kirsch, F.-P., Rathjen, F. G.
(2001). Targeted ablation of NrCAM or ankyrin-B results in disorganized lens fibers leading to cataract formation. JCB
154: 187-196
[Abstract]
[Full Text]
-
Le, A.-C. N., Musil, L. S.
(2001). A novel role for FGF and extracellular signal-regulated kinase in gap junction-mediated intercellular communication in the lens. JCB
154: 197-216
[Abstract]
[Full Text]
-
Gong, X., Wang, X., Han, J., Niesman, I., Huang, Q., Horwitz, J.
(2001). Development of Cataractous Macrophthalmia in Mice Expressing an Active MEK1 in the Lens. IOVS
42: 539-548
[Abstract]
[Full Text]
-
Pal, J. D., Liu, X., Mackay, D., Shiels, A., Berthoud, V. M., Beyer, E. C., Ebihara, L.
(2000). Connexin46 mutations linked to congenital cataract show loss of gap junction channel function. Am. J. Physiol. Cell Physiol.
279: C596-C602
[Abstract]
[Full Text]
-
Landesman, Y., Goodenough, D. A., Paul, D. L.
(2000). Gap Junctional Communication in the Early Xenopus Embryo. JCB
150: 929-936
[Abstract]
[Full Text]
-
Yang, D.-I, Louis, C. F.
(2000). Molecular Cloning of Ovine Connexin44 and Temporal Expression of Gap Junction Proteins in a Lens Cell Culture. IOVS
41: 2658-2664
[Abstract]
[Full Text]
-
Xu, X., Ebihara, L.
(1999). Characterization of a Mouse Cx50 Mutation Associated with the No2 Mouse Cataract. IOVS
40: 1844-1850
[Abstract]
[Full Text]
-
Srinivas, M., Costa, M., Gao, Y., Fort, A., Fishman, G. I, Spray, D. C
(1999). Voltage dependence of macroscopic and unitary currents of gap junction channels formed by mouse connexin50 expressed in rat neuroblastoma cells. J. Physiol.
517: 673-689
[Abstract]
[Full Text]
-
Pal, J. D., Berthoud, V. M., Beyer, E. C., Mackay, D., Shiels, A., Ebihara, L.
(1999). Molecular mechanism underlying a Cx50-linked congenital cataract. Am. J. Physiol. Cell Physiol.
276: C1443-C1446
[Abstract]
[Full Text]
-
Zhou, L., Kasperek, E. M., Nicholson, B. J.
(1999). Dissection of the Molecular Basis of pp60v-src Induced Gating of Connexin 43 Gap Junction Channels. JCB
144: 1033-1045
[Abstract]
[Full Text]
-
Baruch, A., Greenbaum, D., Levy, E. T., Nielsen, P. A., Gilula, N. B., Kumar, N. M., Bogyo, M.
(2001). Defining a Link between Gap Junction Communication, Proteolysis, and Cataract Formation. J. Biol. Chem.
276: 28999-29006
[Abstract]
[Full Text]
-
Yin, X., Gu, S., Jiang, J. X.
(2001). The Development-associated Cleavage of Lens Connexin 45.6 by Caspase-3-like Protease Is Regulated by Casein Kinase II-mediated Phosphorylation. J. Biol. Chem.
276: 34567-34572
[Abstract]
[Full Text]