Biomedical subjects

Neal S Peachey

Publications and source records attributed to Neal S Peachey.

At least 19 recordsLinked to original sources

PubMed2026

GWAS Meta-analysis Identifies Novel Associated Loci and Points to Causal Tissues in Central Serous Chorioretinopathy.

OBJECTIVE: To define CSC genetic architecture and identify implicated ocular tissues, cell types, genes, and circulating proteins. DATA SOURCES: Genome-wide data were assembled from FinnGen, All of Us, Mass General Brigham Biobank, Million Veteran Program, and a Dutch chronic CSC cohort. Serum protein quantitative trait loci, human single-cell ocular atlases, and UK Biobank macular optical coherence tomography (OCT) imaging were used for downstream analyses. STUDY SELECTION: Five European-ancestry cohorts with genome-wide data and cohort-specific CSC case-control definitions were included, comprising 2,584 cases and 1,044,455 controls. Variants present in at least 2 cohorts were meta-analyzed. DATA EXTRACTION AND SYNTHESIS: Cohort-level GWASs were adjusted for age, age squared, sex, genotyping array or batch, and 10 genetic principal components, then combined using fixed-effects inverse-variance meta-analysis. Post-GWAS analyses included gene prioritization, colocalization, Mendelian randomization, single-cell disease-relevance scoring, and testing of a CSC genetic risk score in UK Biobank OCT images. MAIN OUTCOMES AND MEASURES: Genome-wide significant CSC loci, effector genes and proteins, tissue and cell-type enrichment, and CSC-relevant OCT abnormalities. RESULTS: Across 11,068,938 variants, 10 loci reached genome-wide significance (P < 5 × 10-8), including 3 novel loci near TGFB1, LINC00551, and LOC105375630 and 7 replicated loci near CFH, CD46, NOTCH4, PREX1, PTPRB, GATA5, and TNFRSF10A. Integrative analyses prioritized 10 candidate effector genes. Colocalization and Mendelian randomization implicated circulating TNFRSF10A, TGFB1, and CASP10 levels. Single-cell analyses localized genetic risk to sclera (P = 2.0 × 10-4) and vascular endothelial cells (P = 4.0 × 10-4), with fibroblast enrichment. In UK Biobank, OCT abnormalities were more frequent in the top vs bottom 1% of CSC genetic risk (18 of 109 [16.5%] vs 8 of 134 [6.0%]; odds ratio, 4.05; 95% CI, 1.65-10.87; P = .002). CONCLUSIONS AND RELEVANCE: In this GWAS meta-analysis, CSC susceptibility localized predominantly to scleral and vascular biology rather than primary retinal pigment epithelial dysfunction. These findings support CSC as a sclerovascular disorder and nominate complement regulation, endothelial signaling, and extracellular matrix pathways for future study.

Journal Article↗

PubMed2006

Bilateral macular lesions in a 10-year-old girl.

PURPOSE: To report a previously undescribed macular dystrophy. DESIGN: Single descriptive case report. METHODS: Presentation of clinical findings, including ophthalmoscopy, fluorescein angiography, full-field and multifocal electroretinography (ERG), optical coherence tomography (OCT), and visual fields. RESULTS: A 10 year-old Caucasian girl had peculiar reddish blotchy macular lesions bilaterally, associated with decreased visual acuity, and no family history of similar lesions. Fluorescein angiography was inconclusive and showed mottled hyperfluorescence in the macula. The full-field electroretinogram was normal, but multifocal ERG revealed diminished waveforms centrally. CONCLUSION: This is possibly a new macular dystrophy, the nature of which remains to be determined.

Child↗

PubMed2006

Neuronal pentraxins mediate synaptic refinement in the developing visual system.

Neuronal pentraxins (NPs) define a family of proteins that are homologous to C-reactive and acute-phase proteins in the immune system and have been hypothesized to be involved in activity-dependent synaptic plasticity. To investigate the role of NPs in vivo, we generated mice that lack one, two, or all three NPs. NP1/2 knock-out mice exhibited defects in the segregation of eye-specific retinal ganglion cell (RGC) projections to the dorsal lateral geniculate nucleus, a process that involves activity-dependent synapse formation and elimination. Retinas from mice lacking NP1 and NP2 had cholinergically driven waves of activity that occurred at a frequency similar to that of wild-type mice, but several other parameters of retinal activity were altered. RGCs cultured from these mice exhibited a significant delay in functional maturation of glutamatergic synapses. Other developmental processes, such as pathfinding of RGCs at the optic chiasm and hippocampal long-term potentiation and long-term depression, appeared normal in NP-deficient mice. These data indicate that NPs are necessary for early synaptic refinements in the mammalian retina and dorsal lateral geniculate nucleus. We speculate that NPs exert their effects through mechanisms that parallel the known role of short pentraxins outside the CNS.

Animals↗

PubMed2006

Visual cortical plasticity following unilateral sensorimotor cortical lesions in the neonatal rat.

Previous work has shown that unilateral sensorimotor cortex (SMC) lesions in newborn rats resulted in an apparent shift of the motor cortex map in the spared hemisphere, particularly of the hindlimb cortex. In view of such findings, the present study was initiated to determine if the visual cortex located both ipsilateral and contralateral to neonatal SMC, or contralateral to occipital cortical (OC) lesions, would show similar remodeling. Visual evoked potentials (VEPs) were used to map the visual cortex electrophysiologically. The results show an expansion of the visual cortex, in both the contralateral and ipsilateral hemisphere, into normally motor cortical areas in adult animals that had sustained unilateral neonatal unilateral SMC lesions. In contrast, similar changes were not seen within the spared visual cortex after unilateral occipital cortical lesions, suggesting that the shift in the visual map was specifically in response to the SMC lesion and was not a generalized response to neonatal cortical damage. Histological analysis showed a functional expansion in the rostral boundary of visual cortex with no corresponding cytoarchitectural alterations.

Animals↗

PubMed2006

Functional abnormalities in the retinal pigment epithelium of CFTR mutant mice.

In response to light, the mouse retinal pigment epithelium (RPE) generates a series of slow changes in potential that are referred to as the c-wave, fast oscillation (FO) and light peak (LP) of the electroretinogram (ERG). While the FO is known to reflect a Cl(-) conductance generated at the basal membrane of the RPE, the specific channel (s) underlying this potential has not been identified. In the present study we examined two strains of mice with cftr mutations to define the contribution that cystic fibrosis transmembrane regulator (CFTR)-mediated Cl(-) conductance makes to the mouse ERG. Responses obtained from cftr(Delta508/Delta508) mice exhibited an overall reduction in all components generated by the RPE in response to light without alteration of the luminance response function. Responses obtained from cftr(-/-) mice were also reduced in amplitude. These results illustrate the usefulness of ERG analysis of mice deficient in ion channels that are expressed in the RPE, and indicate that CFTR contributes to the generation of RPE-driven ERG components, but that it is not the sole generator of any one of these components.

Animals↗

PubMed2006

Mutation screen of the cone-specific gene, CLUL1, in 376 patients with age-related macular degeneration.

Clusterin is a secreted glycoprotein expressed ubiquitously in many tissues that appears to function as a molecular chaperone capable of protecting stressed proteins. It is upregulated in many different forms of neurodegeneration and is thought to represent a defense response against neuronal damage. Clusterin has been found to be a common protein identified in drusen preparations isolated from the retina of donor eyes of patients with age-related macular degeneration (AMD), the leading cause of blindness in the elderly population of developed countries. A retina-specific clusterin-like protein (CLUL1) showing nearly 25% identity to clusterin at the protein level was recently cloned and shown to be expressed specifically in cone photoreceptor cells. For these reasons, we investigated CLUL1 as a candidate gene for AMD. A mutation screen of the entire coding region of the CLUL1 gene in 376 unrelated patients with AMD uncovered three sequence variations, one isocoding change and two intronic changes. One intronic change appears significantly less frequent in patients with the more severe forms of AMD than in control subjects, suggesting that this variant may reduce the risk for AMD or may be linked to a nearby variant that may reduce AMD risk. Variant alleles of the CLUL1 gene were found; however, none are considered pathogenic. None of the variants identified are predicted to create or destroy splice donor or acceptor sites based on splice-site prediction software.

Aged↗

PubMed2006

The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1).

Mutations in VMD2, encoding bestrophin (best-1), cause Best vitelliform macular dystrophy (BMD), adult-onset vitelliform macular dystrophy (AVMD), and autosomal dominant vitreoretinochoroidopathy (ADVIRC). BMD is distinguished from AVMD by a diminished electrooculogram light peak (LP) in the absence of changes in the flash electroretinogram. Although the LP is thought to be generated by best-1, we find enhanced LP luminance responsiveness with normal amplitude in Vmd2-/- mice and no differences in cellular Cl- currents in comparison to Vmd2+/+ littermates. The putative Ca2+ sensitivity of best-1, and our recent observation that best-1 alters the kinetics of voltage-dependent Ca2+ channels (VDCC), led us to examine the role of VDCCs in the LP. Nimodipine diminished the LP, leading us to survey VDCC beta-subunit mutant mice. Lethargic mice, which harbor a loss of function mutation in the beta4 subunit of VDCCs, exhibited a significant shift in LP luminance response, establishing a role for Ca2+ in LP generation. When stimulated with ATP, which increases [Ca++]I, retinal pigment epithelial cells derived from Vmd2-/- mice exhibited a fivefold greater response than Vmd2+/+ littermates, indicating that best-1 can suppress the rise in [Ca2+]I associated with the LP. We conclude that VDCCs regulated by a beta4 subunit are required to generate the LP and that best-1 antagonizes the LP luminance response potentially via its ability to modulate VDCC function. Furthermore, we suggest that the loss of vision associated with BMD is not caused by the same pathologic process as the diminished LP, but rather is caused by as yet unidentified effects of best-1 on other cellular processes.

Adenosine Triphosphate↗

PubMed2005

Light-induced exacerbation of retinal degeneration in a rat model of Smith-Lemli-Opitz syndrome.

Potentiation of retinal degeneration by intense light exposure, and its amelioration by an antioxidant, were studied in a rat model of Smith-Lemli-Opitz syndrome (SLOS), in comparison with normal (control) Sprague-Dawley rats. The SLOS model is created by treating rats with AY9944, a selective inhibitor of cholesterol synthesis at the level of 3beta-hydroxysterol-Delta7-reductase. A subset of rats was treated with dimethylthiourea (DMTU), a synthetic antioxidant, 24 and 1 hr prior to light exposure. Half of the animals (+/-DMTU) were exposed to intense, constant, green light (24hr, 1700lx, 490-580 nm), while the others were maintained in darkness. Subsequently all animals were returned to dim cyclic light (20-40 lx, 12 hr light-12 hr dark) for 2 weeks, after which electroretinograms were recorded. One eye from each rat was taken for histological and quantitative morphometric analyses; sterol analysis was performed on retinas from contralateral eyes. HPLC analysis confirmed the accumulation of 7-dehydrocholesterol (7DHC) in retinas of AY9944-treated rats; cholesterol represented >99% of the sterol in control retinas. Histology of retinas from unexposed, AY9944-treated rats (6-week-old) was normal. In contrast, age-matched, light-exposed rats exhibited massive photoreceptor cell loss in both the superior and inferior hemispheres, and concomitant rod and cone dysfunction. The severity and geographic extent of the damage was far greater than that observed in normal albino rats exposed to the same conditions. DMTU pre-treatment largely prevented these degenerative changes. These findings indicate that the AY9944-induced rat SLOS model is hypersensitive to intense light-induced retinal damage, relative to normal rats. DMTU protection against light-induced damage implicates free radical-based oxidation in the retinal degeneration process. Furthermore, the use of green light (corresponding to the absorption maxima of rhodopsin) implicates rhodopsin in the initiation of the pathobiological mechanism. We propose that generation of cytotoxic oxysterols (by-products of 7DHC oxidation) is an integral part of retinal cell death in the SLOS rat model, which is exacerbated by intense light. Furthermore, the results predict light-dependent potentiation of retinal degeneration in SLOS patients, and the possible ameliorative effects of antioxidant therapy.

Animals↗

PubMed2005

Insulin receptor substrate 2 is essential for maturation and survival of photoreceptor cells.

Insulin receptor substrates (Irs-proteins) integrate signals from the insulin and insulin-like growth factor-1 (IGF1) receptors with other processes to control cellular growth, function, and survival. Here, we show that Irs2 promoted the maturation and survival of photoreceptors in the murine retina immediately after birth. Irs2 was mainly localized to the outer plexiform layer as well as to photoreceptor inner segments. It was also seen in ganglion cells and inner plexiform layer but in smaller amounts. Compared with control littermates, Irs2 knock-out mice lose 10% of their photoreceptors 1 week after birth and up to 50% by 2 weeks of age as a result of increased apoptosis. The surviving photoreceptor cells developed short organized segments, which displayed proportionally diminished but otherwise normal electrical function. However, IGF1-stimulated Akt phosphorylation was barely detected, and cleaved/activated caspase-3 was significantly elevated in isolated retinas of Irs2-/- mice. When diabetes was prevented, which allowed the Irs2-/- mice to survive for 2 years, most photoreceptor cells were lost by 16 months of age. Because apoptosis is the final common pathway in photoreceptor degeneration, pharmacological strategies that increase Irs2 expression or function in photoreceptor cells could be a general treatment for blinding diseases such as retinitis pigmentosa.

Age Factors↗

PubMed2005

Cochlin deposits in the trabecular meshwork of the glaucomatous DBA/2J mouse.

Cochlin deposits were observed in the trabecular meshwork (TM) of 8-month-old glaucomatous DBA/2J mice, coincident with the reported onset of increased intraocular pressure and optic nerve damage. An age-dependent increase in cochlin was observed up to 10 months of age and was paralleled by a decrease in type II collagen. Similar expression patterns exist in the TM of humans with primary open-angle glaucoma. Cochlin deposits, absent in non-glaucomatous mouse and human TM, may disrupt the TM extracellular matrix and obstruct aqueous humor circulation. Studies of DBA/2J mice offer promise for understanding the role cochlin may play in glaucoma.

Aging↗

PubMed2005

Ocular abnormalities in Large(myd) and Large(vls) mice, spontaneous models for muscle, eye, and brain diseases.

Here we demonstrate previously unreported ocular defects in mice homozygous for a new allele of the Large gene, veils, and for Large(myd) mice. Clinically, vitreal fibroplasia and retinal vessel tortuosity and fluorescein leakage are observed. These vascular defects may be due to the extreme disorganization of the astrocytic template on which endothelial cells migrate in the retina. Abnormal electroretinograms recorded from Large(vls) or Large(myd) mice are accompanied by disorganization of the outer plexiform layer (OPL) with a dramatic reduction in the number of synaptic complexes. In both mutants, the internal limiting membrane (ILM) is disrupted with ectopic cells in the vitreous. Interestingly, while all components of the dystrophin glycoprotein complex are present at reduced levels in the OPL, they were absent in the ILM of affected mice. Finally, hypoglycosylation of alpha-dystroglycan previously implicated in muscle and brain defects is also observed in the retina and may contribute to the ocular abnormalities.

Animals↗

PubMed2004

Proteomics reveal Cochlin deposits associated with glaucomatous trabecular meshwork.

The etiology of primary open angle glaucoma, a leading cause of age-related blindness, remains poorly defined, although elevated intraocular pressure (IOP) contributes to the disease progression. To better understand the mechanisms causing elevated IOP from aqueous humor circulation, we pursued proteomic analyses of trabecular meshwork (TM) from glaucoma and age-matched control donors. These analyses demonstrated that Cochlin, a protein associated with deafness disorder DFNA9, is present in glaucomatous but absent in normal TM. Cochlin was also detected in TM from the glaucomatous DBA/2J mouse preceding elevated IOP but found to be absent in three other mouse lines that do not develop elevated IOP. Histochemical analyses revealed co-deposits of Cochlin and mucopolysaccharide in human TM around Schlemm's canal, similar to that observed in the cochlea in DFNA9 deafness. Purified Cochlin was found to aggregate after sheer stress and to induce the aggregation of TM cells in vitro. Age-dependent in vivo increases in Cochlin were observed in glaucomatous TM, concomitant with a decrease in type II collagen, suggesting that Cochlin may disrupt the TM architecture and render components like collagen more susceptible to degradation and collapse. Overall, these observations suggest that Cochlin contributes to elevated IOP in primary open angle glaucoma through altered interactions within the TM extracellular matrix, resulting in cell aggregation, mucopolysaccharide deposition, and significant obstruction of the aqueous humor circulation.

Adult↗

PubMed2004

Retinal abnormalities associated with the G90D mutation in opsin.

Several mutations in the opsin gene have been associated with congenital stationary night blindness, considered to be a relatively nonprogressive disorder. In the present study, we examined the structural and functional changes induced by one of these mutations, i.e., substitution of aspartic acid for glycine at position 90 (G90D). Transgenic mice were created in which the ratio of transgenic opsin transcript to endogenous was 0.5:1, 1.7:1, or 2.5:1 and were studied via light and electron microscopy, immunocytochemistry, electroretinography (ERG), and spectrophotometry. Retinas with transgenic opsin levels equivalent to one endogenous allele (G0.5) appeared normal for a period of about 3-4 months, but at later ages there were disorganized, shortened rod outer segments (ROS), and a loss of photoreceptor nuclei. Higher levels of G90D opsin expression produced earlier signs of retinal degeneration and more severe disruption of photoreceptor morphology. Despite these adverse effects, the mutation had a positive effect on the retinas of rhodopsin knockout (R-/-) mice, whose visual cells fail to form ROS and rapidly degenerate. Incorporation of the transgene in the null background (G+/-/R-/- or G+/+/R-/-) led to the development of ROS containing G90D opsin and prolonged survival of photoreceptors. Absorbance spectra measured both in vitro and in situ showed a significant reduction of more than 90% in the amount of light-sensitive pigment in the retinas of G+/+/R-/- mice, and ERG recordings revealed a >1 log unit loss in sensitivity. However, the histological appearances of the retinas of these mice show no significant loss of photoreceptors and little change in the lengths of their outer segments. These findings suggest that much of the ERG sensitivity loss derives from the reduced quantal absorption that results from a failure of G90D opsin to bind to its chromophore and form a normal complement of light-sensitive visual pigment.

Animals↗

PubMed2004

Contribution of Kir4.1 to the mouse electroretinogram.

PURPOSE: The electroretinogram (ERG) represents the combination of several distinct cellular processes and conductances. Here, we define the contribution that K+ conductance through Kir4.1 channels makes to the mouse ERG. METHODS: To obtain mice expressing different levels of Kir4.1, we mated Kir4.1+/- mice and used PCR to identify Kir4.1+/- and Kir4.1+/+ littermates. In addition, we mated Kir4.1+/- males with females homozygous for the nob (no b-wave) defect, which eliminates post-receptoral contributions to the ERG. After overnight dark adaptation, mice were anesthetized and ERGs were recorded to 7 min stimuli, to focus on slow ERG components, or to strobe flash stimuli, to examine earlier ERG components. RESULTS: The amplitudes of the ERG c-wave and the fast oscillation, measured from the c-wave peak, were significantly larger in Kir4.1+/- mice than in Kir4.1+/+ littermates. In comparison, the amplitude of the light peak, the other main component generated by the retinal pigment epithelium in response to light, did not differ between Kir4.1+/- and Kir4.1+/+ mice. The amplitude of slow PIII, revealed by the nob genetic background, was reduced in Kir4.1+/- mice. CONCLUSIONS: These results indicate that a cornea-negative potential, generated by Kir4.1, normally opposes a positive polarity conductance that is generated by the apical membrane of the retinal pigment epithelium to form the c-wave measured at the corneal surface.

Animals↗

PubMed2004

Retinal degeneration in a rodent model of Smith-Lemli-Opitz syndrome: electrophysiologic, biochemical, and morphologic features.

OBJECTIVE: To assess the electrophysiologic, histologic, and biochemical features of an animal model of Smith-Lemli-Opitz syndrome (SLOS). METHODS: Sprague-Dawley rats were treated with AY9944, a selective inhibitor of 3beta-hydroxysterol-Delta(7)-reductase (the affected enzyme in SLOS). Dark- and light-adapted electroretinograms were obtained from treated and control animals. From each animal, 1 retina was analyzed by microscopy, and the contralateral retina plus serum samples were analyzed for sterol composition. The main outcome measures were rod and cone electroretinographic amplitudes and implicit times, outer nuclear layer (ONL) thickness, rod outer segment length, pyknotic ONL nucleus counts, and the 7-dehydrocholesterol/cholesterol mole ratio in the retina and serum. RESULTS: By 10 weeks' postnatal age, rod and cone electroretinographic wave amplitudes in AY9944-treated animals were significantly reduced and implicit times were significantly increased relative to controls. Maximal rod photoresponse and gain values were reduced approximately 2-fold in treated animals relative to controls. The ONL thickness and average rod outer segment length were reduced by approximately 18% and 33%, respectively, and ONL pyknotic nucleus counts were approximately 4.5-fold greater in treated animals relative to controls. The retinal pigment epithelium of treated animals contained massive amounts of membranous/lipid inclusions not routinely observed in controls. The 7-dehydrocholesterol/cholesterol mole ratios in treated retinas and serum samples were approximately 5:1 and 9:1, respectively, whereas the ratios in control tissues were essentially zero. CONCLUSIONS: This rodent model exhibits the key biochemical hallmarks associated with SLOS and displays electrophysiologic deficits comparable to or greater than those observed in the human disease. Clinical Relevance These results predict retinal degeneration in patients with SLOS, particularly those with the more severe (type II) form of the disease, and may be more broadly relevant to other inborn errors of cholesterol biosynthesis. This animal model may also be of use in evaluating therapeutic treatments for SLOS and in understanding the slow phototransduction kinetics observed in patients with SLOS.

Animals↗

PubMed2004

A model of best vitelliform macular dystrophy in rats.

PURPOSE: The VMD2 gene, mutated in Best macular dystrophy (BMD) encodes bestrophin, a 68-kDa basolateral plasma membrane protein expressed in retinal pigment epithelial (RPE) cells. BMD is characterized by a depressed light peak (LP) in the electro-oculogram. Bestrophin is thought to be the Cl channel that generates the LP. The goal was to generate an animal model of BMD and to determine the effects of bestrophin overexpression on the RPE-generated components of the ERG. METHODS: Bestrophin or bestrophin mutants (W93C or R218C) were overexpressed in the RPE of rats by injection of replication-defective adenovirus. Immunofluorescence microscopy and ERG recordings were used to study subsequent effects. RESULTS: Bestrophin was confined to the basolateral plasma membrane of the RPE. Neither wild-type (wt) nor mutant bestrophin affected the a- or b-waves of the ERG. Wt bestrophin, however, increased the c-wave and fast oscillation (FO), but not the LP. In contrast, both mutants had little or no effect on the c-wave and FO, but did reduce LP amplitude. LP amplitudes across a range of stimuli were not altered by wt bestrophin, though the luminance response function was desensitized. LP response functions were unaffected by bestrophin R218C but were significantly altered by bestrophin W93C. CONCLUSIONS: A model of BMD was developed in the present study. Because overexpression of wt bestrophin shifted luminance response but did not alter the range of LP response amplitudes, the authors conclude that the rate-limiting step for generating LP amplitude occurs before activation of bestrophin or that bestrophin does not directly generate the LP conductance.

Adenoviridae↗

PubMed2003

Light-evoked responses of the mouse retinal pigment epithelium.

In response to light, the retinal pigment epithelium (RPE) generates a series of slow potentials that can be recorded as the c-wave, fast oscillation (FO), and light peak (LP) of the electroretinogram (ERG). As these potentials can be related to specific cellular events, they provide information about RPE function and how that may be altered by disease or experimental manipulation. In the present study we describe a noninvasive means for recording the light-evoked responses of the mouse RPE and use this to define the stimulus-response properties of the major components in three inbred strains of mice (BALBc/ByJ, C57BL/6J, and 129/SvJ) and two mouse mutants that reduce activity in the rod pathway. All of the major ERG components generated by the RPE are readily measured in the mouse. In albino strains (BALBc/ByJ and 129/SvJ) the intensity-response functions for the c-wave, FO, and LP are shifted toward lower intensities in comparison to those for C57BL/6J mice. Each of these components was markedly reduced in mice lacking transducin in which rod phototransduction is interrupted, indicating that they reflect primarily rod photoreceptor activity. All components were observed in no b-wave (nob) mutant mice, indicating that inner retinal activity does not make a major contribution to these potentials. Further studies of mutant mice will allow us to define the functional consequences of gene manipulation on RPE function and to evaluate specific hypotheses regarding the generation of ERG components.

Animals↗

PubMed2003

Loss of bipolar cells resulting from the expression of bcl-2 directed by the IRBP promoter.

We have recently noted marked reductions in the electroretinographic (ERG) b-wave in HIBA transgenic mice expressing bcl-2 under control of the human IRBP promoter. These electrophysiological results are unexpected as this promoter has been shown to specifically target transgene expression to the rod and cone photoreceptors. Here, we have carried out a series of studies to better understand this result. ERGs were recorded from three lines of HIBA transgenic mice. Mice with higher levels of transgene expression developed progressive photoreceptor degeneration, and an associated reduction in the ERG a-wave. These higher-expressing lines also exhibited a severe reduction in the ERG b-wave that affected both rod- and cone-mediated responses. These mice were mated to L7 transgenic mice, which express beta-galactosidase in bipolar cells. In double transgenic mice, the ERG b-wave reduction was associated with a decrease in the number of bipolar cells in the inner retina. These results indicate that bcl-2, targeted to photoreceptors, can induce bipolar cell degeneration, and indicate that the potential benefit for bcl-2 in treating hereditary retinal disease appears limited.

Animals↗