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Membrane frizzled-related protein is necessary for the normal development and maintenance of photoreceptor outer segments

Published online by Cambridge University Press:  01 July 2008

JUNGYEON WON ,
RICHARD S. SMITH ,
NEAL S. PEACHEY ,
JIANG WU ,
WANDA L. HICKS ,
JÜRGEN K. NAGGERT  and
PATSY M. NISHINA
JUNGYEON WON
Affiliation:
The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine
RICHARD S. SMITH
Affiliation:
The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine
NEAL S. PEACHEY
Affiliation:
Research Service, Cleveland VA Medical Center, Cleveland, Ohio Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio
JIANG WU
Affiliation:
Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio
WANDA L. HICKS
Affiliation:
The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine
JÜRGEN K. NAGGERT
Affiliation:
The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine
PATSY M. NISHINA*
Affiliation:
The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine
*
*Address correspondence and reprint requests to: Patsy M. Nishina, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609. E-mail: [email protected]
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Abstract

A 4 base pair deletion in a splice donor site of the Mfrp (membrane-type frizzled-related protein) gene, herein referred to as Mfrprd6/rd6, is predicted to lead to the skipping of exon 4 and photoreceptor degeneration in retinal degeneration 6 (rd6) mutant mice. Little, however, is known about the function of the protein or how the mutation causes the degenerative retinal phenotype. Here we examine ultrastructural changes in the retina of Mfrprd6/rd6 mice to determine the earliest effects of the mutation. We also extend the reported observations of the expression pattern of the dicistronic Mfrp/C1qtnf5 message and the localization of these and other retinal pigment epithelium (RPE) and retinal proteins during development and assess the ability of RPE cells to phagocytize outer segments (OSs) in mutant and wild-type (WT) mice. At the ultrastructural level, OSs do not develop normally in Mfrprd6/rd6 mutants. They are disorganized and become progressively shorter as mutant mice age. Additionally, there are focal areas in which there is a reduction of apical RPE microvilli. At P25, the rod electroretinogram (ERG) a-wave of Mfrprd6/rd6 mice is reduced in amplitude by ~50% as are ERG components generated by the RPE. Examination of β-catenin localization and Fos and Tcf-1 expression, intermediates of the canonical Wnt pathway, showed that they were not different between mutant and WT mice, suggesting that MFRP may operate through an alternative pathway. Finally, impaired OS phagocytosis was observed in Mfrprd6/rd6 mice both in standard ambient lighting conditions and with bright light exposure when compared to WT controls.

Keywords

MfrpC1qtnf5Retinal pigment epitheliumPhagocytosisOuter segments
Type
Research Articles
Information
Visual Neuroscience , Volume 25 , Issue 4 , July 2008 , pp. 563 - 574
Copyright
Copyright © Cambridge University Press 2008

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References

Ayala-Ramirez, R., Graue-Wiechers, F., Robredo, V., Amato-Almanza, M., Horta-Diez, I. & Zenteno, J.C. (2006). A new autosomal recessive syndrome consisting of posterior microphthalmos, retinitis pigmentosa, foveoschisis, and optic disc drusen is caused by a MFRP gene mutation. Molecular Vision 12, 1483–1489.Google ScholarPubMed
Ayyagari, R., Mandal, M.N., Karoukis, A.J., Chen, L., Mclaren, N.C., Lichter, M., Wong, D.T., Hitchcock, P.F., Caruso, R.C., Moroi, S.E., Maumenee, I.H. & Sieving, P.A. (2005). Late-onset macular degeneration and long anterior lens zonules result from a CTRP5 gene mutation. Investigative Ophthalmology & Visual Science 46, 3363–3371.CrossRefGoogle ScholarPubMed
Besharse, J.C., Hollyfield, J.G. & Rayborn, M.E. (1977). Turnover of rod photoreceptor outer segments. II. Membrane addition and loss in relationship to light. Journal of Cell Biology 75, 507–527.CrossRefGoogle ScholarPubMed
Bonilha, V.L., Rayborn, M.E., Saotome, I., Mcclatchey, A.I. & Hollyfield, J.G. (2006). Microvilli defects in retinas of ezrin knockout mice. Experimental Eye Research 82, 720–729.CrossRefGoogle ScholarPubMed
Cheng, T., Peachey, N.S., Li, S., Goto, Y., Cao, Y. & Naash, M.I. (1997). The effect of peripherin/rds haploinsufficiency on rod and cone photoreceptors. Journal of Neuroscience 17, 8118–8128.CrossRefGoogle ScholarPubMed
Collin, G.B., Cyr, E., Bronson, R., Marshall, J.D., Gifford, E.J., Hicks, W., Murray, S.A., Zheng, Q.Y., Smith, R.S., Nishina, P.M. & Naggert, J.K. (2005). Alms1-disrupted mice recapitulate human Alstrom syndrome. Human Molecular Genetics 14, 2323–2333.CrossRefGoogle ScholarPubMed
Duncan, J.L., Lavail, M.M., Yasumura, D., Matthes, M.T., Yang, H., Trautmann, N., Chappelow, A.V., Feng, W., Earp, H.S., Matsushima, G.K. & Vollrath, D. (2003). An RCS-like retinal dystrophy phenotype in mer knockout mice. Investigative Ophthalmology & Visual Science 44, 826–838.CrossRefGoogle ScholarPubMed
Farjo, R., Skaggs, J.S., Nagel, B.A., Quiambao, A.B., Nash, Z.A., Fliesler, S.J. & Naash, M.I. (2006). Retention of function without normal disc morphogenesis occurs in cone but not rod photoreceptors. Journal of Cell Biology 173, 59–69.Google Scholar
Hawes, N.L., Chang, B., Hageman, G.S., Nusinowitz, S., Nishina, P.M., Schneider, B.S., Smith, R.S., Roderick, T.H., Davisson, M.T. & Heckenlively, J.R. (2000). Retinal degeneration 6 (rd6): A new mouse model for human retinitis punctata albescens. Investigative Ophthalmology & Visual Science 41, 3149–3157.Google ScholarPubMed
Hayward, C., Shu, X., Cideciyan, A.V., Lennon, A., Barran, P., Zareparsi, S., Sawyer, L., Hendry, G., Dhillon, B., Milam, A.H., Luthert, P.J., Swaroop, A., Hastie, N.D., Jacobson, S.G. & Wright, A.F. (2003). Mutation in a short-chain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration: a genetic model for age-related macular degeneration. Human Molecular Genetics 12, 2657–2667.Google Scholar
Kameya, S., Hawes, N.L., Chang, B., Heckenlively, J.R., Naggert, J.K. & Nishina, P.M. (2002). Mfrp, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6. Human Molecular Genetics 11, 1879–1886.Google Scholar
Katoh, M. (2001). Molecular cloning and characterization of MFRP, a novel gene encoding a membrane-type Frizzled-related protein. Biochemical and Biophysical Research Communications 282, 116–123.CrossRefGoogle ScholarPubMed
Lee, Y., Kameya, S., Cox, G.A., Hsu, J., Hicks, W., Maddatu, T.P., Smith, R.S., Naggert, J.K., Peachey, N.S. & Nishina, P.M. (2005). Ocular abnormalities in Large(myd) and Large(vls) mice, spontaneous models for muscle, eye, and brain diseases. Molecular and Cellular Neuroscience 30, 160–172.Google Scholar
Mandal, M.N., Vasireddy, V., Jablonski, M.M., Wang, X., Heckenlively, J.R., Hughes, B.A., Reddy, G.B. & Ayyagari, R. (2006 a). Spatial and temporal expression of MFRP and its interaction with CTRP5. Investigative Ophthalmology & Visual Science 47, 5514–5521.Google Scholar
Mandal, M.N., Vasireddy, V., Reddy, G.B., Wang, X., Moroi, S.E., Pattnaik, B.R., Hughes, B.A., Heckenlively, J.R., Hitchcock, P.F., Jablonski, M.M. & Ayyagari, R. (2006 b). CTRP5 is a membrane-associated and secretory protein in the RPE and ciliary body and the S163R mutation of CTRP5 impairs its secretion. Investigative Ophthalmology & Visual Science 47, 5505–5513.CrossRefGoogle ScholarPubMed
Molday, R.S. (1994). Peripherin/rds and rom-1: Molecular properties and role in photoreceptor degeneration. Progress in Retinal & Eye Research 13, 271–299.CrossRefGoogle Scholar
Nandrot, E.F., Kim, Y., Brodie, S.E., Huang, X., Sheppard, D. & Finnemann, S.C. (2004). Loss of synchronized retinal phagocytosis and age-related blindness in mice lacking alphavbeta5 integrin. Journal of Experimental Medicine 200, 1539–1545.CrossRefGoogle ScholarPubMed
Peachey, N.S., Goto, Y., Al-Ubaidi, M.R. & Naash, M.I. (1993). Properties of the mouse cone-mediated electroretinogram during light adaptation. Neuroscience Letters 162, 9–11.Google Scholar
Russ, P.K., Davidson, M.K., Hoffman, L.H. & Haselton, F.R. (1998). Partial characterization of the human retinal endothelial cell tight and adherens junction complexes. Investigative Ophthalmology & Visual Science 39, 2479–2485.Google ScholarPubMed
Shu, X., Tulloch, B., Lennon, A., Vlachantoni, D., Zhou, X., Hayward, C. & Wright, A.F. (2006). Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5. Human Molecular Genetics 15, 1680–1689.Google Scholar
Strauss, O. (2005). The retinal pigment epithelium in visual function. Physiological Reviews 85, 845–881.Google Scholar
Subrayan, V., Morris, B., Armbrecht, A.M., Wright, A.F. & Dhillon, B. (2005). Long anterior lens zonules in late-onset retinal degeneration (L-ORD). American Journal of Ophthalmology 140, 1127–1129.CrossRefGoogle ScholarPubMed
Sundin, O.H., Leppert, G.S., Silva, E.D., Yang, J.M., Dharmaraj, S., Maumenee, I.H., Santos, L.C., Parsa, C.F., Traboulsi, E.I., Broman, K.W., Dibernardo, C., Sunness, J.S., Toy, J. & Weinberg, E.M. (2005). Extreme hyperopia is the result of null mutations in MFRP, which encodes a Frizzled-related protein. Proceedings of the National Academy of Sciences of the United States of America 102, 9553–9558.CrossRefGoogle ScholarPubMed
Travis, G.H., Brennan, M.B., Danielson, P.E., Kozak, C.A. & Sutcliffe, J.G. (1989). Identification of a photoreceptor-specific mRNA encoded by the gene responsible for retinal degeneration slow (rds). Nature 338, 70–73.CrossRefGoogle Scholar
Wu, J., Marmorstein, A.D., Kofuji, P. & Peachey, N.S. (2004 a). Contribution of Kir4.1 to the mouse electroretinogram. Molecular Vision 10, 650–654.Google Scholar
Wu, J., Peachey, N.S. & Marmorstein, A.D. (2004 b). Light-evoked responses of the mouse retinal pigment epithelium. Journal of Neurophysiology 91, 1134–1142.CrossRefGoogle ScholarPubMed