We report the chromosomal localization, mutant gene identification, ophthalmic appearance, histology, and functional analysis of two new hereditary mouse models of retinal degeneration not having the Pde6brd1("r", "rd", or "rodless") mutation. One strain harbors an autosomal recessive mutation that maps to mouse chromosome 5. Sequence analysis showed that the retinal degeneration is caused by a missense point mutation in exon 13 of the beta-subunit of the rod cGMP phosphodiesterase (beta-PDE) gene (Pde6b). The gene symbol for this strain was set as Pde6brd10, abbreviated rd10 hereafter. Mice homozygous for the rd10 mutation showed histological changes at postnatal day 16 (P16) of age and sclerotic retinal vessels at four weeks of age, consistent with retinal degeneration. Retinal sections were highly positive for TUNEL and activated caspase-3 immunoreactivity, specifically in the outer nuclear layer (ONL). ERGs were never normal, but rod and cone ERG a- and b-waves were easily measured at P18 and steadily declined over 90% by two months of age. Protein extracts from rd10 retinas were positive for beta-PDE immunoreactivity starting at about the same time as wild-type (P10), though signal averaged less than 40% of wild-type. Interestingly, rearing rd10 mice in total darkness delayed degeneration for at least a week, after which morphological and functional loss progressed irregularly. With the second strain, a complementation test with rd1 mice revealed that the retinal degeneration phenotype observed represents a possible new allele of Pde6b. Sequencing demonstrated a missense point mutation in exon 16 of the beta-subunit of rod phosphodiesterase gene, different from the point mutations in rd1 and rd10. The gene symbol for this strain was set as Pde6bnmf137, abbreviated nmf137 hereafter. Mice homozygous for this mutation showed retinal degeneration with a mottled retina and white retinal vessels at three weeks of age. The exon 13 missense mutation (rd10) is the first known occurrence of a second mutant allele spontaneously arising in the Pde6b gene in mice and may provide a model for studying the pathogenesis of autosomal recessive retinitis pigmentosa (arRP) in humans. It may also provide a better model for experimental pharmaceutical-based therapy for RP because of its later onset and milder retinal degeneration than rd1 and nmf137.

The Jackson Laboratory, having the world's largest collection of mouse mutant stocks and genetically diverse inbred strains, is an ideal place to discover genetically determined eye variations and disorders. In this paper, we list and describe mouse models for ocular research available from Mouse Eye Mutant Resource at The Jackson Laboratory. While screening mouse strains and stocks at The Jackson Laboratory (TJL) for genetic mouse models of human ocular disorders, we have identified numerous spontaneous or naturally occurring mutants. We characterized these mutants using serial indirect ophthalmoscopy, fundus photography, electroretinography (ERG) and histology, and performed genetic analysis including linkage studies and gene identification. Utilizing ophthalmoscopy, electroretinography, and histology, to date we have discovered 109 new disorders affecting all aspects of the eye including the lid, cornea, iris, lens, and retina, resulting in corneal disorders, glaucoma, cataracts, and retinal degenerations. The number of known serious or disabling eye diseases in humans is large and affects millions of people each year. Yet research on these diseases frequently is limited by the obvious restrictions on studying pathophysiologic processes in the human eye. Likewise, many human ocular diseases are genetic in origin, but appropriate families often are not readily available for genetic studies. Mouse models of inherited ocular disease provide powerful tools for rapid genetic analysis, characterization, and gene identification. Because of the great similarity among mammalian genomes, these findings in mice have direct relevance to the homologous human conditions.

Neuromuscular degeneration, nmd, is a spontaneous autosomal recessive mutation in the mouse producing progressive hindlimb impairment caused by spinal muscular atrophy. We used an intersubspecific intercross between B6.BKs-nmd2J/+ and Mus musculus castaneus (CAST/Ei) to map the nmd mutation to mouse Chromosome (Chr) 19 with the most likely gene order: nmd(D19Se12, Pygm)-Cnt f -Pomc2-D19Mi t I6 -Cyp2c-Got1 . nmd maps near muscle deficient, mdf and has a very similar clinical phenotype, but allele tests and histological differences suggest that nmd is a distinct mutation at a different locus. Although closely linked, nmd recombined with the candidate genes muscle glycogen phosphorylase, Pygm, and ciliary neurotrophic factor, Cng

In the outcrossing of a new recessive mouse mutation causing hair loss, a new wavy-coated phenotype appeared. The two distinct phenotypes were shown to be alternative manifestations of the same gene mutation and attributable to a single modifier locus. The new mutation, curly bare (cub), was mapped to distal Chr 11 and the modifier (mcub) was mapped to Chr 5. When homozygous for the recessive mcub allele, cub/cub mice appear hairless. A single copy of the dominant Mcub allele confers a full, curly coat in cub/cub mice. Reciprocal transfer of full-thickness skin grafts between mutant and control animals showed that the skin phenotype was tissue autonomous. The hairless cub/cub mcub/mcub mice show normal contact sensitivity responses to oxazolone. The similarity of the wavy coat phenotype to those of Tgfa and Egfr mutations and the map positions of cub and mcub suggest candidate genes that interact in the EGF receptor signal transduction pathway.

Piracetam is a nootropic agent that has been shown to improve cognitive performance in a number of animal model systems. Piracetam is reported to be used widely as a means of improving cognitive function in children with Down's syndrome (DS). In order to provide a preclinical assessment of the potential efficacy of piracetam, we examined the effects of a dose range of piracetam in the Ts65Dn mouse model of DS. Ts65Dn mice are trisomic for a region of mouse chromosome 16 with homology to human chromosome 21. Daily piracetam treatment at doses of 0, 75, 150, and 300 mg/kg ip was initiated in 6-week-old male Ts65Dn and euploid control mice. Following 4 weeks of treatment, mice were tested in the visible and hidden-platform components of the Morris water maze and were placed overnight in computerized activity chambers to assess effects on overall activity. Piracetam treatment was continued through the 4 weeks of testing. In control mice, 75 and 150 mg/kg/day piracetam improved performance in both the visible- and hidden-platform tasks. Although low doses of piracetam reduced search time in the visible-platform component in Ts65Dn mice, all piracetam doses prevented trial-related improvements in performance in Ts65Dn mice. The 300-mg/kg/day-piracetam dose was associated with a reversal of the nocturnal spontaneous hyperactivity in Ts65Dn. These data do not provide support for piracetam treatment for individuals with DS.

The Jackson Laboratory, having the world's largest collection of mouse mutant stocks and genetically diverse inbred strains, is an ideal place to look for genetically determined eye variations and disorders. Through ophthalmoscopy, electroretinography and histology, we have discovered disorders affecting all aspects of the eye including the lid, cornea, iris, lens and retina, resulting in corneal disorders, cataracts, glaucoma and retinal degenerations. Mouse models of retinal degeneration have been investigated for many years in the hope of understanding the causes of photoreceptor cell death. Sixteen naturally occurring mouse mutants that manifest degeneration of photoreceptors in the retina with preservation of all other retinal cell types have been found: retinal degeneration (formerly rd, identical with rodless retina, r, now Pde6b(rd1)); Purkinje cell degeneration (pcd); nervous (nr); retinal degeneration slow (rds, now Prph(Rd2)); retinal degeneration 3 (rd3); motor neuron degeneration (mnd); retinal degeneration 4 (Rd4); retinal degeneration 5 (rd5, now tub); vitiligo (vit, now Mitf(mi-vit)); retinal degeneration 6 (rd6); retinal degeneration 7 (rd7, now Nr2e3(rd7)); neuronal ceroid lipofuscinosis (nclf); retinal degeneration 8 (rd8); retinal degeneration 9 (Rd9); retinal degeneration 10 (rd10, now Pde6b(rd10)); and cone photoreceptor function loss (cpfl1). In this report, we first review the genotypes and phenotypes of these mutants and second, list the mouse strains that carry each mutation. We will also provide detailed information about the cpfl1 mutation. The phenotypic characteristics of cpfl1 mice are similar to those observed in patients with complete achromatopsia (ACHM2, OMIM 216900) and the cpfl1 mutation is the first naturally-arising mutation in mice to cause cone-specific photoreceptor function loss. cpfl1 mice may provide a model for congenital achromatopsia in humans.

Mice altered by transgenesis or gene targeting ("knockouts") have increasingly been employed as alternative effective tools in elucidating the genetic basis of neurophysiology and behavior. Standardization of specific behavioral paradigms and phenotyping strategies will ensure that these behavioral mouse mutants offer robust models for evaluating the efficacy of novel therapeutics in the treatment of hereditary neurological disorders. The Induced Mutant Resource (IMR) at The Jackson Laboratory (Bar Harbor, Maine, USA) imports, cryopreserves, develops, maintains, and distributes to the research community biomedically valuable stocks of transgenic and targeted mutant mice. Information on behavioral and neurological strains-including a phenotypic synopsis, husbandry requirements, strain availability, and genetic typing protocols-is available through the IMR database (http://www.jax.org/resources/documents/imr/). A current catalog of available strains is readily accessible via the JAX Mice Web site at http://jaxmice.jax.org/index.shtml. In addition, The Jackson Laboratory is now home to TBASE (http://tbase.jax.org/), a comprehensive, community database whose primary focus is on mouse knockouts. TBASE accommodates an exhaustive bibliographical resource for transgenic and knockout mice and provides a detailed phenotypic characterization of numerous behavioral knockouts that is primarily extracted from the literature. Concerted efforts to merge the two resources into a new, schematically reformed database are underway.