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.
Scientific report
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.
Lab staff
Professor: Patsy M. Nishina, Ph.D.Research Assistant I: Ronald E. Hurd, B.S.
Laboratory Technician: Jieping Wang, B.A., Bernard FitzMaurice
Visiting Investigators: John R. Heckenlively, M.D., University of Michigan Kellogg Eye Center, Ann Arbor, Mich., Steven Nusinowitz, Ph.D., Jules Stein Eye Institute, Los Angeles, Calif.
Publication listings
Thompson DA, Khan NW, Othman MI, Chang B, Jia L, Grahek G, Wu Z, Hiriyanna S, Nelissery J, Li T, Khanna H, Colosi P, Swaroop A, Heckenlively Jr. 2012. Rd9 is a naturally occurring mouse model of a common form of retinitis pigmentosa caused by mutations in RPGR-ORF15. PLoS One 7: e35865. PMCID: PMC3341386
Pang JJ, Deng WT, Dai X, Lei B, Everhart D, Umino Y, Li J, Zhang K, Mao S, Boye SL, Liu L, Chiodo VA, Liu X, Shi W, Tao Y, Chang B, Hauswirth WW. 2012. AAV-mediated cone rescue in a naturally occurring mouse model of CNGA3-achromatopsia. PLoS One 7: e35250. PMCID: PMC 3324465
Merath KM, Chang B, Dubielzig R, Jeannotte R, Sidjanin DJ. 2011. A spontaneous mutation in Srebf2 leads to cataracts and persistent skin wounds in the lens opacity 13 (lop13) mouse. Mamm Genome 22: 661-673. PMCID: PMC3251904
Kolandaivelu S, Chang B, Ramamurthy V. 2011. Rod phosphodiesterase-6 (PDE6) catalytic subunits restore cone function in a mouse model lacking cone PDE6 catalytic subunit. J Biol Chem 286: 33252-33259. PMCID: PMC3190866
Pang JJ, Dai X, Boye SE, Barone I, Boye SL, Mao S, Everhart D, Dinculescu A, Liu L, Umino Y, Lei B, Chang B, Barlow R, Strettoi E, Hauswirth WW. 2011. Long-term retinal function and structure rescue using capsid mutant AAV8 vector in the rd10 mouse, a model of recessive retinitis pigmentosa. Mol Ther 19: 234-242. PMCID: PMC3034861
Li X, Li W, Dai X, Kong F, Zheng Q, Zhou X, Lü F, Chang B, Rohrer B, Hauswirth WW, Qu J, Pang JJ. 2011. Gene therapy rescues cone structure and function in the 3-month old rd12 mouse: a model for midcourse RPE65 leber congenital amaurosis. Invest Ophthalmol Vis Sci 52: 7-15. PMCID: PMC3053305
Won J, Shi LY, Hicks W, Wang J, Hurd R, Naggert JK, Chang B, Nishina PM. 2011. Mouse model resources for vision research. J Ophthalmol 2011: 391384. PMCID: PMC2968714
Liang L, Liegel R, endres B, Ronchetti A, Chang B, Sidjanin DJ. 2011. Functional analysis of the Hsf4(lop11) allele responsible for cataracts in lop11 mice. Mol Vis 17: 3062-3071. PMCID: PMC3233385
Friedman JS, Chang B, Krauth DS, Lopez I, Waseem NH, Hurd RE, Feathers KL, Branham KE, Shaw M, Thomas GE, Brooks MJ, Liu C, Bakeri HA, Campos MM, Maubaret C, Webster AR, Rodriguez IR, Thompson DA, Bhattacharya SS, Koenekoop RK, Heckenlively JR, Swaroop A. 2010. Loss of iysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice. Proc Natl Acad Sci 107: 15523-15528. PMCID: PMC2932565
Scott-McKean JJ, Chang B, Hurd RE, Nusinowitz S, Schmidt C, Davisson MT, Costa AC. 2010. The mouse model of Down syndrome Ts65Dn presents visual deficits as assessed by pattern visual evoked potentials. Invest Ophthalmol Vis Sci 51:3300-3308. PMCID: PMC2874110
Pang J, Boye SE, Lei B, Boye SL, Everhart D, Ryals R, Umino Y, Rohrer B, Alexander J, Li J, Dai X, Li Q, Chang B, Barlow R, Hauswirth WW. 2010. Self-complementary AAV-mediated gene therapy resotres cone function and prevents cone degeneration in two models of Rpe65 deficiency. Gene Ther 17: 815-826. PMCID: PMC3014850
Pang JJ, Alexander J, Lei B, Deng W, Zhang K, Li Q, Chang B, Hauswirth WW. 2010. Achromatopsia as a potential candidate for gene therapy. Adv Exp Med Biol 664:639-646.
Lively GD, Jiang B, Hedberg-Buenz A, Chang B, Petersen GE, Wang K, Kuehn MH, Anderson M. 2009. Genetic dependence of central corneal thickness among inbred strains of mice. Invest Ophthalmol Vis Sci 51:160-171. PMCID: PMC2869057
Chang B, Grau T, Dangel S, Hurd R, Jurklies B, Sener EC, Andreasson S, Dollfus H, Baumann B, Bolz S, Artemyev N, Kohl S, Heckenlively J, Wissinger B. 2009. A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene. PNAS USA 106(46):19581-19586. PMCID: PMC2780790
Deng WT, Sakurai K, Liu J, Dinculescu A, Li J, Pang J, Min SH, Chiodo VA, Boye SL, Chang B, Kefalov VJ, Hauswirth WW. 2009. Functional interchangeability of rod and cone transducin alpha-subunits. PNAS USA 106(42):17681-1786. PMCID: PMC2758286
Mao M, Thedens DR, Chang B, Harris BS, Zheng QY, Johnson KR, Donahue LR, Anderson MG. 2009. The podosomal-adaptor protein SH3PXD2B is essential for normal postnatal development. Mamm Genome 20(8):462-475. PMCID: PMC2759419
Li W, Kong F, Li X, Dai X, Liu X, Zheng Q, Wu R, Zhou X, Lu F, Chang B, Li Q, Hauswirth WW, Qu J, Pang JJ. 2009. Gene therapy following subretinal AAV5 vector delivery is not affected by a previous intravitreal AAV5 vector administration in the partner eye. Mol Vis 15:267-275. PMCID: PMC2633462
Chang B, Mandal MN, Chavali VR, Hawes NL, Khan NW, Hurd RE, Smith RS, Davisson ML, Kopplin L, Klein BE, Klein R, Iyengar SK, Heckenlively JR, Ayyagari R. 2008. Age-related retinal degeneration (arrd2) in a novel mouse model due to a nonsense mutation in the Mdm1 gene. Hum Mol Genet 17:3929-3941. PMCID: PMC2638579
Anderson MG, Hawes NL, Trantow CM, Chang B, John SW. 2008. Iris phenotypes and pigment dispersion caused by genes influencing pigmentation. Pigment Cell Melanoma Res 21:565-578. PMCID: PMC2862261
Hu W, Jiang A, Liang J, Meng H, Chang B, Gao H, Qiao X. 2008. Expression of VLDLR in the retina and evolution of subretinal neovascularization in the knockout mouse model's retina angiomatous proliferation. Ophthalmol Vis Sci 49(1):407-415.
Li L, Chang B, Cheng C, Chang D, Hawes NL, Xia C-H, Gong X. 2008. Dense nuclear cataract caused by the gammaB-crystallin S11R point mutations. Invest Ophthalmol Vis Sci 49(1):304-309.
Maddox DM, Vessey KA, Yarbrough GL, Invergo BM, Cantrell DR, Inayat S, Balannik V, Hicks WL, Hawes NL, Byers S, Smith RS, Hurd R, Howell D, Gregg RG, Chang B, Naggert JK, Troy JB, Pinto LH, Nishina PM, McCall MA. 2008. Allelic variance between GRM6 mutants, Grm6nob3 and Grm6nob4 results in differences in retinal ganglion cell visual responses. J Physiol 586:4409-4424. PMCID: PMC2614010
Pang JJ, Boye SL, Kumar A, Dinculescu A, Deng W, Li J, Li Q, Rani A, Foster TC, Chang B, Hawes NL, Boatright JH, Hauswirth WW. 2008. AAV-mediated gene therapy for retinal degeneration in the rd10 mouse containing a recessive PDEbeta mutation. Invest Ophthalmol Vis Sci 49:4278-4283.
Peng YW, Zallocchi M, Meehan DT, Delimont D, Chang B, Hawes N, Wang W, Cosgrove D. 2008. Progressive morphological and functional defects in retinas from alpha1 integrin-null mice. Invest Ophthalmol Vis Sci 49:4647-4654. PMCID: PMC2625300
Xia CH, Liu H, Cheung D, Wang M, Cheng C, Du X, Chang B, Beutler B, Gong X. 2008. A model for familial exudative vitreoretinopathy caused by LPR5 mutations. Hum Mol Genet 17(11):1605-1612. PMCID: PMC2902293
Alexander JJ, Umino Y, Everhart D, Chang B, Min SH, Li Q, Timmers AM, Hawes NL, Pang J-J, Barlow RB, Hauswirth WW. 2007. Restoration of cone vision in a mouse model of achromatopsia. Nat Med 13(6):685-687.
Chang B, Hawes NL, Pardue MT, German AM, Hurd RE, Davisson MT, Nusinowitz S, Rengarajan K, Boyd AP, Sidney SS, Phillips MJ, Stewart RE, Chaudhury R, Nickerson JM, Heckenlively JR, Boatright JH. 2007. Two mouse retinal degenerations caused by missense mutations in the β-subunit of rod cGMP phosphodiesterase gene. Vis Res 47:624-633.
Cideciyan AV, Aleman TS, Jacobson SG, Khanna H, Sumaroka A, Aguirre GK, Schwartz SB, Windsor EA, He S, Chang B, Stone EM, Swaroop A. 2007. Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: Implications for therapy of Leber congenital amaurosis. Hum Mutat 28(11):1074-1083.
Boatright JH, Moring AG, McElroy C, Phillips MJ, Do VT, Chang B, Hawes NL, Boyd AP, Sidney SS, Stewart RE, Minear SC, Chaudhury R, Ciavatta VT, Rodrigues CM, Steer CJ, Nickerson JM, Pardue MT. 2006. Tool from ancient pharmacopoeia prevents vision loss. Mol Vis 12:1706-1714.
Chang B, Dacey MS, Hawes NL, Hitchcock PF, Milam AH, Atmaca-Sonmez P, Nusinowitz S, Heckenlively JR. 2006. Cone photoreceptor function loss-3, a novel mouse model of achromatopsia due to a mutation in Gnat2. Invest Ophthalmol Vis Sci 47(11):5017-5021.
Chang B, Heckenlively JR, Bayley PR, Brecha NC, Davisson MT, Hawes NL, Hirano AA, Hurd RE, Ideda A, Johnson BA, McCall MA, Morgans CW, Nusinowitz S, Peachey NS, Rice DS, Vessesy KA, Gregg RG. 2006. The nob2 mouse, a null mutation in Cacna1f: anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses. Vis Neurosci 23:11-24. PMCID: PMC2831086
Chang B, Khanna H, Hawes N, Jimeno D, He S, Lillo C, Parapuram SK, Cheng H, Scott A, Hurd RE, Sayer JA, Otto EA, Attanasio M, O'Toole JF, Jim G, Shou C, Hildebrandt F, Williams DS, Heckenlively JR, Swaroop A. 2006. In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. Hum Mol Genet 15(11):1847-1857. PMCID: PMC1592550
Elizabeth Rakoczy P, Yu MJ, Nusinowitz S, Chang B, Heckenlively JR. 2006. Mouse models of age-related macular degeneration. Exp Eye Res 82(5):741-752. Review
Friedman JS, Chang B, Kannabiran C, Chakarova C, Singh HP, Jalai S, Hawes NL, Branham K, Othman M, Filippova E, Thompson DA, Webster AR, Andreasson S, Jacobson SG, Bhattacharya SS, Heckenlively JR, Swaroop A. 2006. Premature truncation of a novel protein RD3, exhibiting subnuclear localization is associated with retinal degeneration. Am J Hum Genet 79(6):1059-1070. PMCID: PMC1698706
Kitamura E, Danciger M, Yamashita C, Rao NP, Nusinowitz S, Chang B, Farber DB. 2006. Disruption of the gene encoding the β1-subunit of transducin in the Rd4/+ mouse. Invest Ophthalmol Vis Sci 47(4):1293-1301.
Lei B, Yao G, Zhang K, Hofeldt KJ, Chang B. 2006. Study of rod-and cone-driven oscillatory potentials in mice. Invest Ophthalmol Vis Sci 47(6):2732-2738.
Lyons BL, Smith RS, Hurd RE, Hawes NL, Burzenski LM, Nusinowitz S, Hasham MG, Chang B, Shultz LD. 2006. Deficiency of SHP-1 protein-tyrosine phosphatase in 'viable motheaten' mice results in retinal degeneration. Invest Ophthalmol Vis Sci 47(3):1201-1209.
Nathan J, Reh R, Ankoudinova I, Ankoudinova G, Chang B, Heckenlively J, Hurley JB. 2006. Scotopic and photopic visual thresholds and spatial and temporal discrimination evaluated by behavior of mice in a water maze. Photochem Photobiol 82(6):1489-1494.
Nusinowitz S, Ridder WH 3rd, Pang JJ, Chang B, Noorwez SM, Kaushal S, Hauswirth WW, Heckenlively JR. 2006. Cortical visual function in the rd12 mouse model of leber congenital amarousis (LCA) after gene replacement therapy to restore retinal function. Vis Res 46(22):3926-3934.
Pang JJ, Chang B, Kumar A, Nusinowitz S, Noorwez SM, Li J, Rani A, Foster TC, Chiodo VA, Doyle T, Li H, Malhotra R, Teusner JT, McDowell JH, Min SH, Li Q, Kaushal S, Hauswirth WW. 2006. Gene therapy restores vision-dependent behavior as well as retinal structure and function in a mouse model of RPE65 Leber congenital amaurosis. Mol Ther 13:565-572.
Talamas E, Jackson L, Koeberl M, Jackson T, McElwee JL, Hawes NL, Chang B, Jablonski MM, Sidjanin DJ. 2006. Early transposable element insertion in intron 9 of the Hsf4 gene results in autosomal recessive cataracts in lop11 and Idis1 mice. Genomics 88(1):44-51. PMCID:PMC1509100
Xia CH, Cheung D, Derosa AM, Chang B, Lo WK, White TW, Gong X. 2006. Knock-in of alpha3 connexin prevents severe cataracts caused by an alpha8 point mutation. J Cell Sci 119(Pt 10):2138-2144.
Xia CH, Liu H, Chang B, Cheng C, Cheung D, Wang M, Huang Q, Horowitz J, Gong X. 2006. Arginine 54 and tyrosine 118 residues of A-crystallin are crucial for lens formation and transparency. Invest Ophthalmol Vis Sci 47(7):3004-3010.
Xia CH, Liu H, Wang M, Cheung D, Park A, Yang Y, Du X, Chang B, Beutler B, Gong X. 2006. Characterization of mouse mutants with abnormal RPE cells. Adv Exp Med Biol 572:95-100.
Yao G, Zhang K, Bellassai M, Chang B, Lei B. 2006. Ultraviolet light-induced and green light-induced transient pupillary light reflex in mice. Curr Eye Res 31(11):925-933.
Chang B, Hawes NL, Hurd RE, Wang J, Howell D, Davisson MT, Roderick TH, Nusinowitz S, Heckenlively JR. 2005. Mouse models of ocular diseases. Vis Neurosci 22:587-593.
Pang JJ, Chang B, Hawes NL, Hurd RE, Davisson MT, Li J, Noorwez SM, Malhotra R, McDowell JH, Kaushal S, Hauswirth WW, Nusinowitz S, Thompson DA, Heckenlively JR. 2005. Retinal degeneration 12 (rd12): A new spontaneously arising mouse model for human Leber Congenital Amaurosis (LCA). Mol Vis 11:152-162.
Zheng QY, Yan D, Ouyang XM, Du LL, Yu H, Chang B, Johnson KR, Liu XZ. 2005. Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans. 2005. Hum Mol Genet 14(1):103-111. PMCID: PMC2858222
Donahue LR, Chang B, Subburaman M, Miyakoshi N, Wergedal JE, Baylink DJ, Hawes NL, Rosen CJ, Ward-Bailey P, Zheng QY. 2003. A missense mutation in the mouse Col2al gene causes spondyloepiphyseal dysplasia, hearing loss, and retinoschisis. J Bone Miner Res 18(9):1612-1621. PMCID: PMC2862909
Heckenlively JR, Hawes NL, Friedlander M, Nusinowitz S, Hurd R, Davisson M, Chang B. 2003. Mouse models of subretinal neovascularization with choroidal anastomosis. Retina 23(4):518-522.
Johnson KR, Gagnon LH, Webb LS, Peters LL, Hawes NL, Chang B, Zheng QY. 2003. Mouse models of USH1C and DFNB18: phenotype and molecular analyses of two new spontaneous mutations of the Ush1c gene. Hum Mol Genet 12(23):3075-3086.
Mehalow AK, Kameya S, Smith RS, Hawes NL, Denegre JM, Young JA, Bechtold L, Haider NB, Tepass U, Heckenlively JR, Chang B, Naggert JK, Nishina PM. 2003. CRB1 is essential for external limiting membrane integrity and photoreceptor morphogenesis in the mammalian retina. Hum Mol Genet 12(17):2179-2189.
Anderson MG, Smith RS, Hawes NL, Zabaleta A, Chang B, Wiggs JL, John SW. 2002. Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice. Nat Genet 30: 81-85
Chang B, Hawes NL, Hurd RE, Davisson MT, Nusinowitz S, Heckenlively JR. 2002. Retinal degeneration mutants in the mouse. Vision Res 42:517-525.
Chang B, Wang X, Hawes NL, Ojakian R, Davisson MT, Lo W, Gong X. 2002. A Gja8 (a 8 connexin) point mutation causes functional impairment of a 3 connexin in semi-dominant cataracts of Lop10 mice. Hum Mol Genet 11:507-513.
Kameya S, Hawes NL, Chang B, Heckenlively JR, Naggert JK, Nishina PM. 2002. Mfrp, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6. Hum Mol Genet 11:1879-1886.
Young KA, Berry ML, Mahaffey CL, Saionz JR, Hawes NL, Chang B, Zheng QY, Smith RS, Bronson RT, Nelson RJ, Simpson EM. 2002. Fierce: A new mouse deletion of Nr2e1; violent behaviour and ocular abnormalities are background-dependent. Behav Brain Res 132:145-158. PMCID: PMC2862907