Overview
Glaucoma, macular degeneration and ocular vascular disease are among the leading causes of blindness. Either the diseases themselves or the traits that modify the effects of each disease are genetic. I am working with the John lab to identify new mouse models for eye disorders that correlate with human disease. We are studying both congenital and adult forms of glaucoma. Our research into pigmentary glaucoma, which accounts for about 5% of adult glaucoma cases, seeks to determine what structures are damaged during the early stages of disease, a critical first step for seeking the underlying molecular mechanisms that can lead to translational therapeutic studies.
I am also working with The Jackson Laboratory eye group to identify mutations in the mouse colonies that might serve as useful models for human disease. We are working to develop models for glaucoma, retinal degeneration, ocular neovascularization, age-related macular degeneration, and corneal disease that will provide ways to learn about disease mechanisms and contribute to prevention and better clinical treatments in humans.
Scientific report
Opthalmic Pathology
New ocular phenotypes are frequently identified in spontaneous mutations, in genetically engineered mice, and associated with induced mutagenesis. After assessment of the clinical phenotype, morphologic evaluation of disease evolution provides insight into the consequences of the mutation. Dr. Smith's background in clinical ophthalmology and human and mouse ophthalmic pathology enables him to correlate ocular phenotypes with human disease. Recent collaborative research, described in the following paragraphs, emphasizes the value of this approach.
Glaucoma
Glaucoma is a leading cause of blindness, with an estimated 70 million people worldwide afflicted with this heterogeneous group of diseases. Increased intraocular pressure is a major risk factor for glaucomatous visual loss, but molecular mechanisms that cause increased intraocular pressure and the associated neurodegeneration are complex and poorly understood. Pigmentary glaucoma accounts for about 5 percent of glaucoma in adults. Dr. Simon John's laboratory is studying a model of pigmentary glaucoma in DBA/2J mice, which develop glaucoma around 7-8 months of age associated with progressive loss of retinal ganglion cells and optic nerve degeneration. In addition to studies directly related to pigmentary glaucoma, DBA/2J mice have proven to be very useful models for studying the general effects of increased intraocular pressure on the retina and optic nerve. Over the years, opinions have differed about the initial site of damage in glaucoma. Possibilities include direct effects on the retinal ganglion cells, optic nerve ischemia related to elevated eye pressure, or direct pressure effects on the axons of the optic nerve. Recently, others have suggested that glaucoma is due to disease processes originating in the brain. Determining what structures are damaged during the early stages of disease is a critical first step for seeking the underlying molecular mechanisms that can lead to translational therapeutic studies. Previous work in the John laboratory using DBA/2J mice deficient in the proapoptotic Bcl2-associated X protein (Bax) were protected from retinal ganglion cell death. While the retinal ganglion cells were protected, their axons degenerated. These findings led to a study of where the initial damage occurs, and preliminary results point to axonal damage in the lamina cribrosa as the primary injury. Changes in astrocytes and microglia in this location suggest a complex molecular mechanism for glaucoma damage, which will stimulate our efforts in the coming year.
Mutations in the myocilin (MYOC) gene are an important cause of primary open angle glaucoma (5 percent of all cases) and over 70 mutations in MYOC have been identified in human subjects. However, the precise mechanisms that elevate intraocular pressure in MYOC mutations are unknown. It has been suggested that misfolded MYOC proteins are responsible. This hypothesis was tested by generating mice that had a mutant allele of Myoc (Myoctm1Sj) analogous to a human mutation. Mutant MYOC was not secreted into the aqueous humor of these mice, but accumulated in the iridocorneal angle. However, the accumulating mutant protein did not activate a response to the unfolded protein and failed to elevate intraocular pressure. This suggested that these changes alone are insufficient to cause glaucoma in vivo.
Retinal degeneration
Viable motheaten mice (mev/mev) have severe immune dysfunction due to deficiency of protein tyrosinase phosphatase, non-receptor type 6 (PTPN6 or SHP-1) that is a negative regulator of signal transduction of hematopoietic cells. Fundus examination of SHP-1 mice showed numerous small white spots. Light and transmission electron microscopy revealed severe loss of photoreceptor outer segments and the presence of large macrophages in the subretinal space. SHP-1 protein was expressed primarily in the outer nuclear layer, and increased apoptosis during the time of active retinal degeneration in this location supported the conclusion that SHP-1 has a previously unknown role in retinal homeostasis.
The goals of the Ophthalmic Pathology program are to assist in identification of clinical and morphologic phenotypes in JAX® Mice that may serve as models for human disease. Some specific mouse models of human disease were reviewed in a chapter by members of The Jackson Laboratory eye group and external collaborators in the first new edition since 1982 of The Mouse in Biomedical Research. Glaucoma, retinal degeneration, ocular neovascularization, age-related macular degeneration, and corneal disease in humans can produce severe loss of vision and are important causes of major human visual disabilities. Clinical and morphologic phenotyping continue to play an important role in delineating disease mechanisms and providing knowledge useful in preventing human disease or developing treatments.
Lab staff
Principal Investigator:
Richard S. Smith, M.D., D.Med.Sci.
Histotechnologist:
Barbra Mortimer
Electroretinographer:
Douglas M. Howell
Executive Assistant:
Bethany Preble
Research Administrative Assistant:
Daron McGowan
Publication listings
Publications 2002-Present
Anderson MG, Smith RS, Hawes NL, Zabaleta A, Chang B, Wiggs JL, and John SW. 2002. Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice. Nat Genet 30:81-85.
Mo J., Smith RS, Anderson MG, John SWM, Streilin JW. 2002. Participation of innate immune macrophages in the pathogenesis of pigmentary glaucoma in mice. Invest Ophthalmol Vis Sci 43:S136.
Nishina PM, Hawes NL, Hurd R, Chang B, Smith RS. 2002. Mouse models exhibiting phenotypic characteristics observed in persistent hyperplastic primary vitreous. Invest Ophthalmol Vis Sci 43:S81.
Smith RS, Korb D, and John SW. 2002. A goniolens for clinical monitoring of the mouse iridocorneal angle and optic nerve. Mol Vis 8:26-31. http://www.molvis.org/molvis/v8a4/
Smith RS, Miller JV, and Sundberg JP. 2002. Intraocular teratoma in a mouse. Comp Med 52:68-72.
Young KA, Berry ML, Mahaffey CL, Saionz JR, Hawes NL, Chang B, Zheng QY, Smith RS, Bronson RT, Nelson RJ. 2002. Fierce: a new mouse deletion of Nr2e 1; violent behavior and ocular abnormalities are background dependent. Behav Brain Res 132:145-158.
Ikeda S, Cunningham LA, Boggess D, Hawes N, Hobson CD, Sundberg JP, Naggert JK, Smith RS, Nishina PM. 2003. Aberrant actin cytoskeleton leads to accelerated proliferation of corneal epithelial cells in mice deficient for destrin (actin depolymerizing factor). Hum Mol Genet 12:1029-1037.
Ikeda S, Cunningham LA, Boggess D, Hobson DM, Sundberg JP, Naggert JK, Smith RS, Nishina PM. 2003. Mutations in destrin (actin-depolymerizing factor) lead to corneal epithelial proliferation and neovascularization in the corn1 mouse. Invest Ophthalmol Vis Sci 44:S2147.
John SW, Smith RS, Perkins BD, Gray MP, Savinova OV, Dowling JE, Link BA. 2003. Characterization of the zebrafish bug eye mutation, exploring a genetic model for pressure-induced retinal cell death. Invest Ophthalmol Vis Sci 44:S1125.
Kameya S, Cox GA, Hicks W, Ikeda S, Hurd R, Smith RS, Naggert JK, Nishina PM. 2003. Ocular abnormalities and cardiomyopathy associated with mutations in the mouse large gene. Invest Ophthalmol Vis Sci 44:S3571.
Lehmann OJ, Tuft S, Brice G, Smith R, Blixt A, Bell R, Johansson B, Jordan T, Hitchings RA, Khaw PT, John SW, Carlsson P, Bhattacharya SS. 2003. Novel anterior segment phenotypes resulting from forkhead gene alterations: evidence for cross-species conservation of function. Invest Ophthalmol Vis Sci 44:2627-2633.
Libby RT, Smith RS, Savinova OV, Clark AF, John SWM. 2003. Inducible nitroc oxide synthase (Nos2) is not required for glaucomatous optic nerve damage in DBA/2J mice. Invest Ophthalmol Vis Sci 44:S145.
Libby RT, Smith RS, Savinova OV, Zabaleta A, Martin JE, Gonzalez FJ, John SW. 2003. Modification of ocular defects in mouse developmental glaucoma models by tyrosinase. Science 299:1578-1581.
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 12:2179-2189.
Mo JS, Anderson MG, Gregory M, Smith RS, Savinova OV, Serreze DV, Ksander BR, Streilein JW, John SW. 2003. By altering ocular immune privilege, bone marrow-derived cells pathogenically contribute to DBA/2J pigmentary glaucoma. J Exp Med 197:1335-1344.
Anderson M, Libby RT, Savinova OV, Snow AL, Smith RS, John SWM. 2004. Genetic modifications of glaucomatous phenotypes in C57BL/6J mice. Invest Ophthalmol Vis Sci 45:S4623.
Gould DB, Miceli-Libby L, Savinova OV, Torrado M, Tomarev SI, Smith RS, John SW. 2004. Genetically increasing Myoc expression supports a necessary pathologic role of abnormal proteins in glaucoma. Mol Cell Biol 24:9019-9025.
Libby RT, Li Y, Savinova OV, Barter J, Smith RS, Nichells RW, and John SWM. 2004. BAX is necessary for glaucomatous RGC somal but not axonal degeneration in DBA/2J mice. Invest Ophthalmol Vis Sci 45:S2293.
Link BA, Gray MP, Smith RS, John SW. 2004. Intraocular pressure in zebrafish: Comparison of inbred strains and identification of a reduced melanin mutant with raised IOP. Invest Ophthalmol Vis Sci 45: 4415-4422.
Lyons BL, Smith RS, Hurd RE, Hawes NL, Burzenski LM, Shultz LD. 2004. Retinal degeneration in SHP-1 protein-tyrosine phosphatase-deficient 'viable motheaten' mice. Invest Ophthalmol Vis Sci 45:S3620.
Nishina PM, Young JA, Mehalow AK, Hicks W Smith RS, Naggert JK. 2004. Characterization of gene/gene interactions involving Crb1rd8. Invest Ophthalmol Vis Sci 45:S3715.
Anderson MG, Libby RT, Gould DB, Smith RS, John SW. 2005. High-dose radiation with bone marrow transfer prevents neurodegeneration in an inherited glaucoma. Proc Natl Acad Sci USA 102:4566-4571. http://www.pnas.org/cgi/content/full/102/12/4566
Collin GB, Cyr E, Bronson R, Marshall JD, Gifford EJ, Hicks W, Murray SA, Zheng QY, Smith RS, Nishina PM, Naggert JK. 2005. Alms1-disrupted mice recapitulate human Alstrom syndrome. Hum Mol Genet 14:2323-2333.
Cursiefen C, Ikeda S, Nishina PM, Smith RS, Ikeda A, Jackson D, Mo JS, Chen L, Dana MR, Pytowski B, Kruse FE, Streilein JW. 2005. Spontaneous corneal hem- and lymphangiogenesis in mice with destrinmutation depend on VEGFR3 signaling. Am J Pathol 166:1367-1377.
Gould DB, Phalan FC, Breedveld GJ, van Mil SE, Smith RS, Schimenti JC, Aguglia U, van der Knaap MS, Heutink P, John SW. 2005. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science 308:1167-1171.
Lee Y, Kameya S, Cox GA, Hsu J, Hicks W, Maddatu TP, Smith RS, Naggert JK, Peachey NS, Nishina PM. 2005. Ocular abnormalities in Large(myd) and Large(vls) mice, spontaneous models for muscle, eye, and brain diseases. Mol Cell Neurosci 30;160-172.
Libby RT, Anderson MG, Pang IH, Robinson ZH, Savinova OV, Cosma IM, Snow A, Wilson LA, Smith RS, Clark AF, John SW. 2005. Inherited glaucoma in DBA/2J mice: pertinent disease features for studying the neurodegeneration. Vis Neurosci 22:637-648.
Libby RT, Li Y, Savinova OV, Barter J, Smith RS, Nickells RW, John SW. 2005. Susceptibility to neurodegeration in a glaucoma is modified by Bax gene dosage. PLoS Genet 1:17-26.
Anderson MG, Libby RT, Mao M, Cosma IM, Wilson LA, Smith RS, John SW. 2006. Genetic context determines susceptibility to intraocular pressure elevation in a mouse pigmentary glaucoma. BMC Biol 4:20.
Gould DB, Reedy M, Wilson LA, Smith RS, Johnson RL, John SW. 2006. Mutant myocilin nonsecretion in vivo is not sufficient to cause glaucoma. Mol Cell Biol 26:8427-8436.
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 47:1201-1209.
Gould DB, Libby RT, Phalan C, Smith RS, and John SWM. 2006. Mice with a Col4a1 mutation have phenotypes relevant to human age-related macular degeneration. Invest Ophthalmol Vis Sci S5914.
Gwynn B, Smith RS, Rowe LB, Taylor BA, Peters LL. 2006. A mouse TRAPP-related protein is involved in pigmentation. Genomics 88:196-203.
Lee BY, Mehalow A, Smith RS, Hicks W, Naggert JK and Nishina PM. 2006. Prefoldin5(Pfdn5) is essential for the development of the mouse photoreceptor outer segment (Os). Invest Ophthalmol Vis Sci S2296.
Won J, Smith RS, Peachey NS, Wu J, Hicks WL, Naggert JK and Nishina PM. 2006. Expression and localization of MFRP and C1QTNF5 in the developing retina. Invest Ophthalmol Vis Sci S4201.
Brooks BP, Larson DM, Chan CC, Kjellstrom S, Smith RS, Crawford MA, Lamoreux L, Huizing M, Hess R, Jiao X, Hejtmancik JF, Maminishkis A, John SW, Bush R, Pavan WJ. 2007. Analysis of Ocular Hypopigmentation in Rab38 cht/cht Mice. Invest Opthalmol Vis Sci 48:3905-3913.
Boyd K, Smith RS, Funk AJ, Rogers TD, Dobbins RM. 2007. A closer look: secondary glaucoma more likely. Lab Anim 36:13-4; discussion 14.
Edwards MM, Smith RS, Jordan WL, et al. 2007. Cloning and characterization of a mouse model for retinal vasculopathy: Implications of astrocyte involvement. Invest Ophthalmol Vis Sci 48:1725.
Gould DB, Marchant JK, Savinova OV, Smith RS, John SW. 2007. Col4a1 mutation causes endoplasmic reticulum stress and genetically modifiable ocular dysgenesis. Hum Mol Genet 16:798-807.
Haider NB, Demarco P, Nystuen AM, Huang X, Smith RS, McCall MA, Naggert JK, Nishina PM. 2007. The transcription factor Nr2e3 functions in retinal progenitors to suppress cone cell generation. Vis Neurosci 23:917-929.
Howell GR, Libby RT, Jakobs TC, Smith RS, Phalan FC, Barter JW, Barbay JM, Marchant JK, Mahesh N, Porciatti V, Whitmore AV, Masland RH, John SW. 2007. Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J Cell Biol. 179(7):1523-37.
Howell GR, Libby RT, Marchant JK, Wilson LA, Cosma IM, Smith RS, Anderson MG, John SW. 2007. Absence of glaucoma in DBA/2J mice homozygous for wild-type versions of Gpnmb and Tyrp1. BMC Genet 3(8):45.
Jordan W, Edwards MM, Maddox DM, Smith RS, et al. 2007. Identification of colobomas astrocyte vascular defect 1 (coasvad1), a genetic defect leading to congenital colobomas and vascular abnormalities. Invest Ophthalmol Vis Sci 2977
Libby RT, Howell GR, Cosma IM, Wilson LA, Smith RS and John SWM. 2007. The Wallerian degeneration slow protein lessens glaucoma damage in DBA/2J mice. Invest Ophthalmol Vis Sci 2878.
Libby RT, Howell GR, Pang IH, Savinova OV, Mehalow AK, Barter JW, Smith RS, Clark AF, John SW. 2007. Inducible nitric oxide synthase, Nos2,does not mediate optic neuropathy and retinopathy in the DBA/2J glaucoma model. BMC neuroscience 8(1):108.
Maddox DM, Hicks WL, Okeda A, Ikeda S, Smith RS, el al. 2007. An early stop codon in the giant scaffolding protein synaptic nuclear envelope 2 (Syne2) may lead to altered synapse morphology and disorganization of the outer plexiform layer (OPL) in diminished cone electroretinogram (dice) mice. Invest Ophthalmol Vis Sci 2987.
Won J, Gifford EJ, Smith RS, et al. 2007. Allelic variation suggests TpGrip1 is important for normal outer segments development. Invest Ophthalmol Vis Sci 4490.
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.
Ghim S, Jenson AB, Bubier JA, Silva KA, Smith RS, Sundberg JP. 2008. Cataracts in transgenic mice caused by a human papillomavirus type 18 E7 oncogene driven by KRT1-14. Exp Mol Pathol. 85:77-82.
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(Pt. 18):4409-24.
Verdoni AM, Smith RS, Ikeda A, Ikeda S. 2008. Defects in actin dynamics lead to an autoinflammatory condition through the upregulation of CXCL5. PLoS ONE 3(7):e2701. PMC2442876PM.
Won J, Smith RS, Peachey NS, Wu J, Hicks WL, Naggert JK, Nishina PM. 2008. Membrane frizzled-related protein is necessary for the normal development and maintenance of photoreceptor outer segments. Vis Neurosci. 25(4):563-74.
Books, Book Chapters, and Reviews:
Bechtold L, Smith RS. 2002. Electron microscopy. In: Systematic evaluation of the mouse eye: Anatomy, pathology, and biomethods. Smith RS, John SWM, Nishina PM, Sundberg JP, [eds], Boca Raton, CRC Press, pp. 272-76.
Martin, G, Smith RS. 2002. Cell kinetics, morphometrics, and confocal microscopy. In: Systematic evaluation of the mouse eye: Anatomy, pathology, and biomethods. Smith RS, John SWM, Nishina PM, Sundberg JP, [eds], Boca Raton, CRC Press, pp. 300-312.
Smith RS, Zabaleta A, et al. 2002. Light microscopy. In: Systematic evaluation of the mouse eye: Anatomy, pathology, and biomethods. Smith RS, John SWM, Nishina PM, Sundberg JP, [eds],Boca Raton, CRC Press, pp. 265-98.
Smith RS, Sundberg JP, et al. 2002. The anterior segment and ocular adnexae. In: Systematic evaluation of the Mouse Eye: Anatomy, pathology, and biomethods. Smith RS, John SWM, Nishina PM, Sundberg JP, [eds], Boca Raton, CRC Press, pp. 3-24.
Smith, RS, John SWM, et al. 2002. The posterior segment and orbit. In: Systematic evaluation of the mouse eye: Anatomy, pathology, and biomethods. Smith RS, John SWM, Nishina PM Sundberg JP, [eds], Boca Raton, CRC Press, pp. 25-44.
Smith RS, Kao W, et al. 2002. Ocular development. In: Systematic evaluation of the mouse eye: Anatomy, pathology, and biomethods. Smith RS, John SWM, Nishina PM, Sundberg JP, [eds], Boca Raton, CRC Press, pp. 45-66.
Smith RS, Sundberg JP. 2002. Strain Background disease characteristics. In: Systematic evaluation of the mouse eye: Anatomy, pathology, and biomethods. Smith RS, John SWM, Nishina PM, Sundberg JP, [eds], Boca Raton, CRC Press, pp. 67-76.
Sundberg JP, Smith RS, et al. 2002. Selection of controls. In: Systematic evaluation of the mouse eye: Anatomy, pathology, and biomethods. Smith RS, John SWM, Nishina PM, Sundberg JP, [eds], Boca Raton, CRC Press, pp. 77-80.
Smith RS, Sundberg JP, et al. 2002. The anterior segment. In: Systematic evaluation of the mouse eye: Anatomy, pathology, and biomethods. Smith RS, John SWM, Nishina PM, Sundberg JP, [eds], Boca Raton, CRC Press, pp. 111-160.
Smith RS. 2002. Choroid, lens, and vitreous. In: Systematic evaluation of the mouse eye: Anatomy, pathology, and biomethods. Smith RS, John SWM, Nishina PM, Sundberg JP, [eds] Boca Raton, CRC Press, pp. 161-94.
Smith RS Hawes NL, et al. 2002. Retina. Systematic evaluation of the mouse eye: Anatomy, pathology, and biomethods. Smith RS, John SWN, Nishina PM, Sundberg JP, [eds], Boca Raton, CRC Press, pp. 195-226.
Smith RS, John SWM, et al. 2002. Optic nerve and orbit. In: Systematic evaluation of the mouse eye: Anatomy, pathology, and biomethods. Smith RS, John SWM, Nishina PM, Sundberg JP, [eds], Boca Raton, CRC Press, pp. 227-250.
Smith RS, Hawes NL, et al. 2002. Photography and necropsy. In: Systematic evaluation of the mouse eye: Anatomy, pathology, and biomethods. Smith RS, John SWM, Nishina PM, Sundberg JP, [eds]. Boca Raton, CRC Press, pp. 251-64.
Smith RS, Zabaleta A, et al. 2002. Light microscopy. In: Systematic evaluation of the mouse eye: Anatomy, pathology, and biomethods. Smith RS, John SWM, Nishina PM, Sundberg JP, [eds], Boca Raton, CRC Press: 265-98.
Gould DB, Smith RS, John SW. 2004. Anterior segment development relevant to glaucoma. Int J Dev Biol 48:1015-1029.
