Genes and pathways in optic fissure closure

Patel, Aara; Sowden, Jane C.

doi:10.1016/j.semcdb.2017.10.010

Cited by 59 publications

(94 citation statements)

References 183 publications

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“…Reduced rates of differentiation were most probably due to an increased number of proliferative EdU + /Ki67 + cells resulting in tissue expansion and bending (arrowhead in Fig J’ and ). Even if these morphological deformations might resemble a coloboma (), which normally results from a failure in ventral fissure closure (Patel & Sowden, ), transverse sections of the optic vesicle depict proper fusion of the ventral fissures in E13.5 Nr2f1 mutants (). Therefore, abnormal optic vesicle morphology observed in Nr2f1 mutants arises most probably from tissue bending due to excessive proliferation and delayed cell differentiation.…”

Section: Resultsmentioning

confidence: 99%

Mouse Nr2f1 haploinsufficiency unveils new pathological mechanisms of a human optic atrophy syndrome

et al. 2019

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Optic nerve atrophy represents the most common form of hereditary optic neuropathies leading to vision impairment. The recently described Bosch‐Boonstra‐Schaaf optic atrophy ( BBSOA ) syndrome denotes an autosomal dominant genetic form of neuropathy caused by mutations or deletions in the NR 2F1 gene. Herein, we describe a mouse model recapitulating key features of BBSOA patients—optic nerve atrophy, optic disc anomalies, and visual deficits—thus representing the only available mouse model for this syndrome. Notably, Nr2f1 ‐deficient optic nerves develop an imbalance between oligodendrocytes and astrocytes leading to postnatal hypomyelination and astrogliosis. Adult heterozygous mice display a slower optic axonal conduction velocity from the retina to high‐order visual centers together with associative visual learning deficits. Importantly, some of these clinical features, such the optic nerve hypomyelination, could be rescued by chemical drug treatment in early postnatal life. Overall, our data shed new insights into the cellular mechanisms of optic nerve atrophy in BBSOA patients and open a promising avenue for future therapeutic approaches.

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Section: Resultsmentioning

confidence: 99%

Mouse Nr2f1 haploinsufficiency unveils new pathological mechanisms of a human optic atrophy syndrome

et al. 2019

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“…As a consequence of the invagination and morphogenesis of the early eye field into a bilayered optic cup, a transient opening known as the choroid fissure forms in the ventral optic cup which enables the hyaloid vasculature to enter the eye, and the optic nerve to exit . The choroid fissure must close such that retina and RPE tissue are properly contained within the eye, and failure of this process results in colobomas (reviewed in Gregory‐Evans et al, 2004; Williamson and FitzPatrick, 2014; Patel and Sowden, 2017) …”

Section: Introductionmentioning

confidence: 99%

“…16 The choroid fissure must close such that retina and RPE tissue are properly contained within the eye, and failure of this process results in colobomas (reviewed in Gregory-Evans et al, 2004; Williamson and FitzPatrick, 2014; Patel and Sowden, 2017). [22][23][24] As mentioned above, previous studies have identified or generated mab21l2 mutant zebrafish 4,6 which display ocular phenotypes. However, these ocular defects have not been fully documented and characterized, which is necessary for these zebrafish models to be useful in providing mechanistic insight into ocular defects in human patients with MAB21L2 mutations, as well as to begin to unravel the functions of the mab21l2 protein during ocular development.…”

Section: Introductionmentioning

confidence: 99%

Zebrafish mab21l2 mutants possess severe defects in optic cup morphogenesis, lens and cornea development

Gath

Gross

2019

Developmental Dynamics

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Background Mutations in MAB21L2 result in severe ocular defects including microphthalmia, anophthalmia, coloboma, microcornea, and cataracts. The molecular and cellular underpinnings of these defects are unknown, as is the normal cellular function of MAB21L2. Zebrafish mab21l2 au10 mutants possess ocular defects resembling those in humans with MAB21L2 mutations, providing an excellent model to characterize mab21l2 functions during eye development. Results mab21l2 −/− mutants possessed a host of ocular defects including microphthalmia and colobomas as well as small, disorganized lenses and cornea dysgenesis. Decreased proliferation, increased cell death, and defects in marker gene expression were detected in the lens. Cell death in the optic stalk was elevated in mab21l2 −/− mutants and the basement membrane between the edges of the choroid fissure failed to break down. Neuronal differentiation in the retina was normal, however. mab21l2 −/− mutant corneas were disorganized, possessed an increased number of cells, some of which proliferated ectopically, and failed to differentiate the corneal stroma. Conclusions mab21l2 function is required for morphogenesis and cell survival in the lens and optic cup, and basement membrane breakdown in the choroid fissure. mab21l2 function also regulates proliferation in the lens and cornea; in its absence, the lens is small and mispatterned, and corneal morphogenesis and patterning are also disrupted.

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“…The presence of multiple patterns of Mendelian inheritance, incomplete penetrance, variable expressivity, genetic heterogeneity, and environmental factors make the genetic investigation of this disease particularly challenging (Chang et al, ; Skalicky et al, ; Williamson & FitzPatrick, ). Although several genes identified in animal studies are critical for optic fissure closure during eye development, very few are known to cause coloboma in humans (Brown et al, ; Patel & Sowden, ). On the other hand, reports of human mutations are often not complemented by experimental mechanistic evidence either in animal models or in cell culture (Bourchany et al, ; Chassaing et al, ; Graham et al, ; Kahrizi et al, ; Martinez‐Garay et al, ; Ng et al, ; Patel & Sowden, ; Wenger et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Although several genes identified in animal studies are critical for optic fissure closure during eye development, very few are known to cause coloboma in humans (Brown et al, ; Patel & Sowden, ). On the other hand, reports of human mutations are often not complemented by experimental mechanistic evidence either in animal models or in cell culture (Bourchany et al, ; Chassaing et al, ; Graham et al, ; Kahrizi et al, ; Martinez‐Garay et al, ; Ng et al, ; Patel & Sowden, ; Wenger et al, ). In many cases, studies on coloboma genetics have focused on a select number of genes, and many have included syndromic conditions with severe ocular phenotypes (e.g., severe microphthalmia and anophthalmia; Gonzalez‐Rodriguez et al, ; Guo, Dai, Huang, Liao, & Bai, ; Mihelec et al, ; Morrison et al, ; Schimmenti et al, ; Williamson & FitzPatrick, ; X. Zhang et al, ; J. Zhou et al, ).…”

Section: Introductionmentioning

confidence: 99%

High‐throughput custom capture sequencing identifies novel mutations in coloboma‐associated genes: Mutation in DNA‐binding domain of retinoic acid receptor beta affects nuclear localization causing ocular coloboma

Kalaskar

Alur

et al. 2019

Human Mutation

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Uveal coloboma is a potentially blinding congenital ocular malformation caused by the failure of optic fissure closure during the fifth week of human gestation. We performed custom capture high-throughput screening of 38 known colobomaassociated genes in 66 families. Suspected causative novel variants were identified in TFAP2A and CHD7, as well as two previously reported variants of uncertain significance in RARB and BMP7. The variant in RARB, unlike previously reported disease mutations in the ligand-binding domain, was a missense change in the highly conserved DNA-binding domain predicted to affect the protein's DNA-binding ability.In vitro studies revealed lower steady-state protein levels, reduced transcriptional activity, and incomplete nuclear localization of the mutant RARB protein compared with wild-type. Zebrafish studies showed that human RARB messenger RNA partially reduced the ocular phenotype caused by morpholino knockdown of rarga gene, a zebrafish homolog of human RARB. Our study indicates that sequence alterations in known coloboma genes account for a small percentage of coloboma cases and that mutations in the RARB DNA-binding domain could result in human disease. K E Y W O R D Scoloboma, custom capture, high-throughput sequencing, retinoic acid receptor beta

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Genes and pathways in optic fissure closure

Cited by 59 publications

References 183 publications

Mouse Nr2f1 haploinsufficiency unveils new pathological mechanisms of a human optic atrophy syndrome

Mouse Nr2f1 haploinsufficiency unveils new pathological mechanisms of a human optic atrophy syndrome

Zebrafish mab21l2 mutants possess severe defects in optic cup morphogenesis, lens and cornea development

High‐throughput custom capture sequencing identifies novel mutations in coloboma‐associated genes: Mutation in DNA‐binding domain of retinoic acid receptor beta affects nuclear localization causing ocular coloboma

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