Ocular abnormalities in Large myd and Large vls mice, spontaneous models for muscle, eye, and brain diseases Yongsuk Lee, a,1 Shuhei Kameya, a,1 Gregory A. Cox, a,1 Jennifer Hsu, b Wanda Hicks, a Terry P. Maddatu, a Richard S. Smith, a Ju ¨ rgen K. Naggert, a Neal S. Peachey, b,c and Patsy M. Nishina a, * a The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA b Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA c Research Service, Cleveland VA Medical Center, Cleveland, OH 44106, USA Received 1 April 2005; revised 3 July 2005; accepted 6 July 2005 Available online 18 August 2005 Here we demonstrate previously unreported ocular defects in mice homozygous for a new allele of the Large gene, veils, and for Large myd mice. Clinically, vitreal fibroplasia and retinal vessel tortuosity and fluorescein leakage are observed. These vascular defects may be due to the extreme disorganization of the astrocytic template on which endothelial cells migrate in the retina. Abnormal electroretinograms recorded from Large vls or Large myd mice are accompanied by disorganization of the outer plexiform layer (OPL) with a dramatic reduction in the number of synaptic complexes. In both mutants, the internal limiting membrane (ILM) is disrupted with ectopic cells in the vitreous. Interestingly, while all components of the dystrophin glycoprotein complex are present at reduced levels in the OPL, they were absent in the ILM of affected mice. Finally, hypoglycosylation of A-dystroglycan previously implicated in muscle and brain defects is also observed in the retina and may contribute to the ocular abnormalities. D 2005 Elsevier Inc. All rights reserved. Introduction Myodystrophy, myd, first described in 1963 (Lane et al., 1976) as a recessive myopathy mapping to chromosome (Chr) 8, was identified as an intragenic deletion within the glycosyltransferase gene, Large (Grewal et al., 2001). Mice homozygous for Large myd have been reported to exhibit runting, an abnormal gait, shortened lifespan, and sensorineural hearing loss. Histologically, Large myd mutants were shown to exhibit focal skeletal muscle lesions characterized by basophilia, variation in fiber size, loss of striation, and central migration of nuclei in all myocytes examined (Mathews et al., 1995). More recently, cardiomyopathy was reported in Large myd mice (Holzfeind et al., 2002). A significant reduction in Large expression caused by a transgene insertion, in the enr strain, also leads to a similar phenotype including defects in nerve conduction, grip strength, and neuromuscular junctions (Leveda- kou et al., 2005). In Large myd and enr mice, mutations in Large are associated with hypoglycosylation of a-dystroglycan, one of the components of the dystrophin glycoprotein complex (DGC; Grewal et al., 2001; Michele et al., 2002; Holzfeind et al., 2002; Levedakou et al., 2005). The DGC is composed of dystrophin and dystrophin- associated proteins (DAPs) including dystroglycans, sarcoglycans, dystrobrevins, and syntrophins. A major role of the DGC is to link cytoskeletal actin to the basal lamina to maintain structural integrity (Ibraghimov-Beskrovnaya et al., 1992; Rybakova et al., 1996). a- Dystroglycan localizes in the extracellular matrix and is required for the assembly of the basal lamina (Henry and Campbell, 1998). Dystrophin gene products and DAPs are also expressed in neuronal tissues. While a global null mutation of dystroglycan results in embryonic lethality (Williamson et al., 1997), deletion of neuron- specific dystroglycan results in migration errors that lead to brain defects similar to those observed in congenital muscular dystrophies such as Fukuyama congenital muscular dystrophy, muscle –eye– brain disease, and Walker–Warburg syndrome (Yoshida et al., 2001; Moore et al., 2002). Interestingly, the products of the affected genes in each of these diseases appear to function as a glycosyltransferase or to otherwise be involved in post-translational modification of glycoproteins, and mutations within these genes all lead to abnormalities of a-dystroglycan in muscle and neuronal tissue (Hayashi et al., 2001; Kano et al., 2002; Beltran-Valero De Bernabe et al., 2002). We have identified a new allele of Large , named veils (vls ), which also results from an intragenic deletion that shares similar phenotypic characteristics to the myd mutation. In contrast to two 1044-7431/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.mcn.2005.07.009 * Corresponding author. Fax: +1 207 288 6077. E-mail address: pmn@aretha.jax.org (P.M. Nishina). 1 These authors contributed equally to this work. Available online on ScienceDirect (www.sciencedirect.com). www.elsevier.com/locate/ymcne YMCNE-01706; No. of pages: 13; 4C: 4, 5, 6, 9, 11 Mol. Cell. Neurosci. 30 (2005) 160 – 172