The Jackson Laboratory

Overview

The objective of our research program is to identify and characterize mouse eye disorders that provide good experimental models for human eye diseases. We have discovered numerous such models by screening and characterizing mutant mice from research and production mouse colonies at The Jackson Laboratory. We have recently characterized mutations that may provide models for retinal degeneration diseases, including retinitis pigmentosa, a group of eye diseases that lead to progressive vision loss and eventual blindness. Other recent discoveries include a model for human achromatopsia, a key feature of which is the absence of color discrimination, that has led to a promising human gene therapy result; a new mutation that results in retinal degeneration, providing a resource for cell transplantation studies; and another that causes a disorder similar to complete congenital stationary night blindness in humans. Our laboratory is also studying the genetic defects in models for glaucoma, cataracts and cone photoreceptor function loss.

Research details

Mouse Models of Eye Diseases

The objective of our research program is to develop new mouse models of inherited human ocular diseases to provide basic research tools for better understanding the diseases, for developing preventive or treatment therapies, and for identifying genes mutated in human ocular disorders. Our program will continue to provide a rich source of these badly needed models that serve as experimental models for human ocular diseases. Some examples of our research results on new models appear below.

The nob2 mouse, a null mutation in Cacna1f: Anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses

The nob2 (no b-wave 2) mutation was initially identified in a recombinant inbred strain, AXB6/PgnJ, established between A/J and C57BL/6J strains. nob2 was discovered as part of our ERG-based screen for spontaneous retinal mutants. All other recombinant inbred strains from the panels (AXB, BXA) had normal b-waves, indicating that the defect in nob2 was the result of a rare spontaneous mutation in the AXB6 line.

The nob2 mutation was mapped between the microsatellite markers DXMit123 and DXMit124, a region that includes Cacna1f (calcium channel, voltage-dependent, alpha 1F subunit). Sequence analysis revealed an insertion of a transposable element (Mus musculus transposon ETn) in exon 2 of the Cacna1f gene. This insertion results in an out-of-frame insertion, which is predicted to produce a stop codon after synthesis of only 32 amino acids. In view of these results, nob2 mice have been renamed Cacna1f ^nob2. Not surprisingly, the b-waves of both the light- and dark-adapted electroretinogram are abnormal in nob2 mice. The outer plexiform layer (OPL) is disorganized, with extension of ectopic neurites through the outer nuclear layer that originate from rod bipolar and horizontal cells, but not from hyperpolarizing bipolar cells. These results indicate that nob2 mice are a valuable model in which to explore the pathophysiological mechanisms associated with CACNA1F mutations causing human CSNB2 (congenital stationary night blindness 2), and the subsequent effects on visual information processing.

A new mouse model of retinal degeneration (rd17)

While screening mouse strains and stocks at The Jackson Laboratory for genetic models of human ocular disorders, we discovered a new mouse retinal degeneration (allele symbol: rd17). rd17 is a new, naturally occurring mouse model of retinal dysfunction and degeneration. Mice homozygous for rd17 show retinal function abnormalities at 3 weeks of age. Electroretinograms of rd17/rd17 mice are never normal. Histology at 2 months of age shows normal retina, but the fundus shows some signs of retinal degeneration (retinal white dots and attenuated vessels). The inheritance pattern of rd17 is autosomal recessive. Initial linkage analysis mapped this new mutation to two chromosomal regions near guanine nucleotide binding protein (Gnat) genes on mouse Chromosome 9, in the Gnat1 region, and on mouse Chromosome 3, in the Gnat2 region. Sequence analysis showed that the dark-adapted ERG abnormality is caused by a sequence alteration in the Gnat1 gene and the light-adapted ERG abnormality is due to the cpfl3 mutation in the Gnat2 gene. The early onset of retinal function abnormalities combined with our genetic data suggests that this is a new digenic retinal disorder not previously described in mouse or human. rd17 may provide a novel mouse model for retinal transplantation studies because its retinal dysfunction would allow the detection of retinal function only from grafted cells.

A new mouse model of cone photoreceptor function loss (cpfl7)

We have found a new mouse mutant with a progressive cone function loss, cpfl7, which is associated with a neurological phenotype seen as an abnormal gait. This new mutation has been named cone photoreceptor function loss 7 (cpfl7) because it is the seventh mutation in mice to affect cone function. Mice homozygous for the cpfl7 mutation show an abnormal light-adapted ERG response and a normal a-wave, but lower b-wave, dark-adapted ERG response starting at 3 weeks of age. Histological results show ganglion cell disruption and retinal segment degeneration in the peripheral retina at 3 months of age. The neurological phenotypes include leg clasping when picked up by the tail and high stepping when the mouse walks on shavings. Genetic analysis shows that this disorder is caused by an autosomal recessive mutation that maps to mouse Chromosome 19. Cone photoreceptor function loss and the neurological phenotype combined with our genetic data suggest that this is a new mutation not previously described in mouse or human. This provides a novel mouse model for a cone photoreceptor function loss associated with neurological defects.

In collaboration with Dr. Patsy Nishina, we are continuing to analyze selected retinal degeneration mutants. In collaboration with Drs. Simon John and Richard Smith, we continue to identify and characterize mouse models for glaucoma. In collaboration with Dr. Xiaohua Gong, University of California, Berkeley, we continue to identify the molecular bases for cataractogenesis in the lenses of connexin mutants and characterize mouse models for cataracts. Other collaborators on specific retinal mutants include Drs. Radha Ayyagari, John Heckenlively and Anand Swaroop, University of Michigan Kellogg Eye Center; Dr. Steven Nusinowitz, Jules Stein Eye Institute; Dr. Jeffrey H. Boatright, Emory Eye Center; Dr. Bo Lei, The University of Missouri Vision Science / VMTH; Drs. Ji-jing Pang and William Hauswirth, University of Florida College of Medicine, Gainesville; and Dr. D.J. Sidjanin, Medical College of Wisconsin, Milwaukee.