Optic nerve axon number in mouse is regulated by PAX2.

BACKGROUND: Papillorenal syndrome is an autosomal-dominant disease caused by mutations in the PAX2 transcription factor gene. Patients often exhibit congenital excavation of the optic nerve and a spectrum of congenital kidney abnormalities. Using a novel mouse model of this syndrome (C57BL/6J PAX2(A220G/+)), we investigated the effect of PAX2 haploinsufficiency on optic nerve axon number. Because PAX2 expression and retinal pigment epithelium pigmentation have a mutually exclusive relationship during development and because tyrosinase (Tyr) has been shown to modify the penetrance of other ocular development genes, we also investigated whether tyrosinase modified the mutant PAX2 phenotype. METHODS: C57BL/6J PAX2(A220G/+)Tyr(+/+) mice were crossed with mice of the same genetic background (C57BL/6J) that are homozygous for an effective null allele of tyrosinase (Tyr(c-2J/c-2J)) over two generations to create mice with four distinct genotypes: PAX2(A220G/+) Tyr(+/c-2J), PAX2(A220G/+) Tyr(c-2J/c-2J), PAX2(+/+) Tyr(c-2J/+), and PAX2(+/+)Tyr(c-2J/c-2J). Mouse optic nerves were examined clinically and histologically. Axon number was assessed in a masked fashion in optic nerves from mice of all four genotypes and compared with parental strains. RESULTS: Mice heterozygous for a PAX2 mutation show reduced optic nerve axon number compared with age-matched controls. Tyrosinase does not appear to modify this phenotype. CONCLUSIONS: Our results show that PAX2 is important in determining axon number in mouse optic nerve. The developmental effects of tyrosinase and PAX2 mutation appear to act via different pathways.

Clinical and genetic heterogeneity of crystalline retinopathies: report of two families without bietti crystalline dystrophy.

PURPOSE: To report variations in the inheritance pattern and clinical presentation of crystalline retinopathies. METHODS: Two different families with crystalline retinopathy were studied with a complete family history and ophthalmologic examination including Goldmann kinetic perimetry and electroretinography. Genetic studies were performed in one of the families. RESULTS: One of the families had a clearly autosomal dominant mode of inheritance while the other family most likely follows an autosomal recessive pattern. Several members in each family had significant retinal pigment epithelial atrophy, intraretinal crystals, relatively pink optic nerves, and paracentral visual field defects, all of which are clinical features resembling those of Bietti crystalline retinopathy. Examination of peripheral leukocytes using transmission electron microscopy in selected affected members showed no evidence of classical lysosomal crystals that are characteristics for Bietti crystalline retinopathy. No pathogenic mutations were identified in the CYP4V2 gene. CONCLUSIONS: Not all crystalline retinopathies are Bietti's. Further genetic, biochemical, and pathologic studies are required to better differentiate between these retinopathies.

Interphotoreceptor retinoid-binding protein (IRBP)-deficient C57BL/6 mice have enhanced immunological and immunopathogenic responses to IRBP and an altered recognition of IRBP epitopes.

Experimental autoimmune uveitis (EAU) and pinealitis (EAP) can be induced in susceptible mice by immunization with immunologically privileged retinal antigens. In the present study, we analyzed the immunologic and immunopathologic responses of mice deficient in the retinal autoantigen interphotoreceptor retinoid-binding protein (IRBP). The consequences of IRBP deficiency on the T-cell repertoire were also investigated. IRBP+/+, IRBP+/- and IRBP-/- mice on the C57BL/6 background were immunized with IRBP or with a pathogenic epitope, IRBP(1-20) peptide in adjuvant, and were evaluated for disease severity and immunological responses. C57BL/6 IRBP-/- mice were completely resistant to EAU and EAP, and had enhanced immunological responses to IRBP and to its pathogenic peptide 1-20, as compared to their IRBP+/+ counterparts. IRBP-/- mice exhibited an altered IRBP epitope recognition. T cell epitope mapping revealed a response to IRBP peptide 271-290 in IRBP-/- mice, that was absent in the wild type. Primed T cells of IRBP-/- mice transferred an exacerbated form of EAU to nai;ve wild type recipients. A gene-dose effect was evident in that C57BL/6 IRBP+/- mice, exhibited intermediate immunological responses and lower disease scores compared to wild type. We conclude that expression of IRBP in target tissues is a necessary prerequisite for disease induction, excluding other retinoid-binding or vision-related proteins as surrogate targets. Furthermore, endogenous expression of IRBP is directly responsible for lowering the threshold of susceptibility to uveitic disease.

Neuroanatomy of the extraocular muscle tendon enthesis in macaque, normal human, and patients with congenital nystagmus.

PURPOSE: To search for the presence of, and qualitatively characterize the microscopic anatomy of, nerve terminals in the tendino-scleral (enthesial) area of the extraocular muscle tendon. METHODS: Extraocular rectus muscle tendino-scleralspecimens from a macaque monkey, a normal human, cadavers, and patients with congenital nystagmus were obtained and studied with transmission electron microscopy. RESULTS: Enthesial neurovascular structures were identified in all specimens. The enthesial area showed structures consisting of myelinated and unmyelinated nerve fibers with associated supporting vascular capillaries. Qualitative analysis showed anomalous neurovascular structures were in the enthesis of patients with congenital nystagmus. CONCLUSIONS: This study confirms the presence of normal and abnormal neural anatomy in the enthesial area of the extraocular muscle tendon. Neurovascular abnormalities in the enthesial part of the extraocular muscle tendon may be a result of, or contribute to, disease pathogenesis. If these structures are related to afferent central nervous system input, then disruption of them during surgery might influence postoperative outcome.