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Optic nerve axon number in mouse is regulated by PAX2.

ABSTRACT: 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.

SUBMITTER: Alur RP

PROVIDER: S-EPMC2435283 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Optic nerve axon number in mouse is regulated by PAX2.

Alur Ramakrishna P RP Cox Terry A TA Crawford Mary Alice MA Gong Xiaohua X Brooks Brian P BP

Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus 20071221 2

<h4>Background</h4>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 relatio ...[more]

PMID: 18083586

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Project description:In this study, we identify genomic regions that modulate the number of necrotic axons in optic nerves of a family of mice, some of which have severe glaucoma, and define a set of high priority positional candidate genes that modulate retinal ganglion cell (RGC) axonal degeneration. A large cohort of the BXD family were aged to greater than 13 months of age. Optic nerves from 74 strains and the DBA/2J (D2) parent were harvested, sectioned, and stained with p-phenylenediamine. Numbers of necrotic axons per optic nerve cross-section were counted from 1 to 10 replicates per genotype. Strain means and standard errors were uploaded into GeneNetwork 2 for mapping and systems genetics analyses (Trait 18614). The number of necrotic axons per nerve ranged from only a few hundred to more than 4,000. Using conventional interval mapping as well as linear mixed model mapping, we identified a single locus on chromosome 12 between 109 and 112.5 Mb with a likelihood ratio statistic (LRS) of ~18.5 (p genome-wide ~0.1). Axon necrosis is not linked to locations of major known glaucoma genes in this family, including Gpnmb, Tyrp1, Cdh11, Pou6f2, and Cacna2d1. This indicates that although these genes contribute to pigmentary dispersion or elevated IOP, none directly modulates axon necrosis. Of 156 positional candidates, eight genes-CDC42 binding protein kinase beta (Cdc42bpb); eukaryotic translation initiation factor 5 (Eif5); BCL2-associated athanogene 5 (Bag5); apoptogenic 1, mitochondrial (Apopt1); kinesin light chain 1 (Klc1); X-ray repair cross complementing 3 (Xrcc3); protein phosphatase 1, regulatory subunit 13B (Ppp1r13b); and transmembrane protein 179 (Tmem179)-passed stringent criteria and are high priority candidates. Several candidates are linked to mitochondria and/or axons, strengthening their plausible role as modulators of ON necrosis. Additional studies are required to validate and/or eliminate plausible candidates. Surprisingly, IOP and ON necrosis are inversely correlated across the BXD family in mice >13 months of age and these two traits share few genes among their top ocular and retinal correlates. These data suggest that the two traits are independently modulated or that a more complex and multifaceted approach is required to reveal their association.

Project description:Optic neuropathies are characterized by degeneration of retinal ganglion cell axonal projections to the brain, including acute conditions like optic nerve trauma and progressive conditions such as glaucoma. Despite different aetiologies, retinal ganglion cell axon degeneration in traumatic optic neuropathy and glaucoma share common pathological signatures. We compared how early pathogenesis of optic nerve trauma and glaucoma influence axon function in the mouse optic projection. We assessed pathology by measuring anterograde axonal transport from retina to superior colliculus, current-evoked optic nerve compound action potential and retinal ganglion cell density 1 week following unilateral optic nerve crush or intraocular pressure elevation. Nerve crush reduced axon transport, compound axon potential and retinal ganglion cell density, which were unaffected by intraocular pressure elevation. Surprisingly, optic nerves contralateral to crush demonstrated 5-fold enhanced excitability in compound action potential compared with naïve nerves. Enhanced excitability in contralateral sham nerves is not due to increased accumulation of voltage-gated sodium channel 1.6, or ectopic voltage-gated sodium channel 1.2 expression within nodes of Ranvier. Our results indicate hyperexcitability is driven by intrinsic responses of αON-sustained retinal ganglion cells. We found αON-sustained retinal ganglion cells in contralateral, sham and eyes demonstrated increased responses to depolarizing currents compared with those from naïve eyes, while light-driven responses remained intact. Dendritic arbours of αON-sustained retinal ganglion cells of the sham eye were like naïve, but soma area and non-phosphorylated neurofilament H increased. Current- and light-evoked responses of sham αOFF-sustained retinal ganglion cells remained stable along with somato-dendritic morphologies. In retinas directly affected by crush, light responses of αON- and αOFF-sustained retinal ganglion cells diminished compared with naïve cells along with decreased dendritic field area or branch points. Like light responses, αOFF-sustained retinal ganglion cell current-evoked responses diminished, but surprisingly, αON-sustained retinal ganglion cell responses were similar to those from naïve retinas. Optic nerve crush reduced dendritic length and area in αON-sustained retinal ganglion cells in eyes ipsilateral to injury, while crush significantly reduced dendritic branching in αOFF-sustained retinal ganglion cells. Interestingly, 1 week of intraocular pressure elevation only affected αOFF-sustained retinal ganglion cell physiology, depolarizing resting membrane potential in cells of affected eyes and blunting current-evoked responses in cells of saline-injected eyes. Collectively, our results suggest that neither saline nor sham surgery provide a true control, chronic versus acute optic neuropathies differentially affect retinal ganglion cells composing the ON and OFF pathways, and acute stress can have near-term effects on the contralateral projection.

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Optic nerve axon number in mouse is regulated by PAX2.

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Optic nerve axon number in mouse is regulated by PAX2.

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