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Mutation in Bmpr1b Leads to Optic Disc Coloboma and Ventral Retinal Gliosis in Mice.

ABSTRACT: Purpose:The clinical phenotype of retinal gliosis occurs in different forms; here, we characterize one novel genetic feature, (i.e., signaling via BMP-receptor 1b). Methods:Mouse mutants were generated within a recessive ENU mutagenesis screen; the underlying mutation was identified by linkage analysis and Sanger sequencing. The eye phenotype was characterized by fundoscopy, optical coherence tomography, optokinetic drum, electroretinography, and visual evoked potentials, by histology, immunohistology, and electron-microscopy. Results:The mutation affects intron 10 of the Bmpr1b gene, which is causative for skipping of exon 10. The expression levels of pSMAD1/5/8 were reduced in the mutant retina. The loss of BMPR1B-mediated signaling leads to optic nerve coloboma, gliosis in the optic nerve head and ventral retina, defective optic nerve axons, and irregular retinal vessels. The ventral retinal gliosis is proliferative and hypertrophic, which is concomitant with neuronal delamination and the reduction of retinal ganglion cells (RGCs); it is dominated by activated astrocytes overexpressing PAX2 and SOX2 but not PAX6, indicating that they may retain properties of gliogenic precursor cells. The expression pattern of PAX2 in the optic nerve head and ventral retina is altered during embryonic development. These events finally result in reduced electrical transmission of the retina and optic nerve and significantly reduced visual acuity. Conclusions:Our study demonstrates that BMPR1B is necessary for the development of the optic nerve and ventral retina. This study could also indicate a new mechanism in the formation of retinal gliosis; it opens new routes for its treatment eventually preventing scar formation in the retina.

SUBMITTER: Yan X

PROVIDER: S-EPMC7329948 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Mutation in Bmpr1b Leads to Optic Disc Coloboma and Ventral Retinal Gliosis in Mice.

Yan Xiaohe X Atorf Jenny J Ramos David D Thiele Frank F Weber Susanne S Dalke Claudia C Sun Minxuan M Puk Oliver O Michel Dian D Fuchs Helmut H Klaften Matthias M Przemeck Gerhard K H GKH Sabrautzki Sibylle S Favor Jack J Ruberte Jesús J Kremers Jan J de Angelis Martin Hrabe MH Graw Jochen J

Investigative ophthalmology & visual science 20200201 2

<h4>Purpose</h4>The clinical phenotype of retinal gliosis occurs in different forms; here, we characterize one novel genetic feature, (i.e., signaling via BMP-receptor 1b).<h4>Methods</h4>Mouse mutants were generated within a recessive ENU mutagenesis screen; the underlying mutation was identified by linkage analysis and Sanger sequencing. The eye phenotype was characterized by fundoscopy, optical coherence tomography, optokinetic drum, electroretinography, and visual evoked potentials, by histo ...[more]

PMID: 32106289

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Project description:PURPOSE: To investigate the genetic basis of recessively-inherited congenital, non syndromic, bilateral, total sclerocornea in two consanguineous pedigrees, one from the Punjab province of Pakistan and the other from the Tlaxcala province of Mexico. METHODS: Ophthalmic examinations were conducted on each family member to confirm their diagnosis and magnetic resonance imaging (MRI) or ultrasonography of the eyes was performed on some family members. Genomic DNA was analyzed by homozygosity mapping using the Affymetrix 6.0 SNP array and linkage was confirmed with polymorphic microsatellite markers. Candidate genes were sequenced. RESULTS: A diagnosis of autosomal recessive sclerocornea was established for 7 members of the Pakistani and 8 members of the Mexican pedigrees. In the Pakistani family we established linkage to a region on chromosome 1p that contained Forkhead Box E3 (FOXE3), a strong candidate gene since FOXE3 mutations had previously been associated with various anterior segment abnormalities. Sequencing FOXE3 identified the previously reported nonsense mutation, c.720C>A, p.C240X, in the Pakistani pedigree and a novel missense mutation which disrupts an evolutionarily conserved residue in the forkhead domain, c.292T>C, p.Y98H, in the Mexican pedigree. Individuals with heterozygous mutations had no ocular abnormalities. MRI or ultrasonography confirmed that the patients with sclerocornea were also aphakic, had microphthalmia and some had optic disc coloboma. CONCLUSIONS: This is the fourth report detailing homozygous FOXE3 mutations causing anterior segment abnormalities in human patients. Previous papers have emphasized aphakia and microphthalmia as the primary phenotype, but we find that the initial diagnosis - and perhaps the only one possible in a rural setting - is one of non-syndromic, bilateral, total sclerocornea. Dominantly inherited anterior segment defects have also been noted in association with heterozygous FOXE3 mutations. However the absence of any abnormalities in the FOXE3 heterozygotes described suggests that genetic background and environmental factors plays a role in the penetrance of the mutant allele.

Project description:The exact mechanisms and temporal sequence of neurodegeneration in multiple sclerosis are still unresolved. The visual pathway including its unmyelinated retinal axons, can serve as a prototypic model of neurodegeneration in experimental optic neuritis. We conducted a longitudinal study combining retinal imaging through optical coherence tomography (OCT) with immunohistochemical analyses of retinal and optic nerve tissue at various time points in experimental autoimmune encephalomyelitis (EAE).Inner retinal layer (IRL) thickness was measured in 30 EAE and 14 healthy control C57BL/6 J mice using OCT. Distribution of marker proteins was assessed by immunofluorescence staining and retinal mRNA levels were assayed using real-time PCR. Histological morphology was evaluated on light and electron microscopy images.Signs of inflammatory edema 11 days post immunisation coincided with IRL thickening, while neuro-axonal degeneration throughout the disease course contributed to IRL thinning observed after 20 days post immunisation. Retinal pathology, including axonal transport impairment, was observed early, prior to cellular infiltration (i.e. T-cells) in the optic nerve 11 days post immunisation. Yet, the effects of early retinal damage on OCT-derived readouts were outweighed by the initial inflammatory edema. Early microglial activation and astrocytosis was detected in the retina prior to retinal ganglion cell loss and persisted until 33 days post immunisation. Müller cell reactivity (i.e. aquaporin-4 and glutamine synthetase decrease) presented after 11 days post immunisation in the IRL. Severe neuro-axonal degeneration was observed in the optic nerve and retina until 33 days post immunisation.Initial signs of retinal pathology subsequent to early glial activity, suggests a need for prophylactic treatment of optic neuritis. Following early inflammation, Müller cells possibly respond to retinal pathology with compensatory mechanisms. Although the majority of the IRL damage observed is likely due to retrograde degeneration following optic neuritis, initial pathology, possibly due to gliosis, may contribute further to IRL thinning. These results add morphological substrate to our OCT findings. The extent and rapid onset of axonal and neuronal damage in this model appears relevant for testing interventions scaled to human optic neuritis.

Dataset Information

Mutation in Bmpr1b Leads to Optic Disc Coloboma and Ventral Retinal Gliosis in Mice.

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Mutation in Bmpr1b Leads to Optic Disc Coloboma and Ventral Retinal Gliosis in Mice.

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