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Qu C.,Wenzhou University | Qu C.,China State Key Laboratory Cultivation Base and Key Laboratory of Vision Science | Qu C.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry | Qu C.,Yale University | And 25 more authors.
Journal of Biological Chemistry | Year: 2016

Retinal ganglion cells (RGCs) are projection neurons in the neural retina that relay visual information from the environment to the central nervous system. The early expression of MATH5 endows the post-mitotic precursors with RGC competence and leads to the activation of Brn3b that marks committed RGCs. Nevertheless, this fate commitment process and, specifically, regulation of Brn3b remain elusive. To explore the molecular mechanisms underlying RGC generation in the mouse retina, we analyzed the expression and function of Fez family zinc finger 2 (FEZF2), a transcription factor critical for the development of projection neurons in the cerebral cortex. Fezf2 mRNA and protein were transiently expressed at embryonic day 16.5 in the inner neuroblast layer and the prospective ganglion cell layer of the retina, respectively. Knockout of Fezf2 in the developing retina reducedBRN3B+cells and increased apoptotic cell markers. Fezf2 knockdown by retinal in utero electroporation diminished BRN3B but not the coexpressed ISLET1 and BRN3A, indicating that the BRN3B decrease was the cause, not the result, of the overall reduction of BRN3B RGCs in the Fezf2 knockout retina. Moreover, the mRNA and promoter activity of Brn3b were increased in vitro by FEZF2, which bound to a 5′ regulatory fragment in the Brn3b genomic locus. These results indicate that transient expression of Fezf2 in the retina modulates the transcription of Brn3b and the survival of RGCs. This study improves our understanding of the transcriptional cascade required for the specification of RGCs and provides novel insights into the molecular basis of retinal development. ©2016 by The American Society for Biochemistry and Molecular Biology, Inc.


Liu Z.,Xiamen University | Qiu F.,Xiamen University | Li J.,Xiamen University | Zhu Z.,Xiamen University | And 13 more authors.
PLoS ONE | Year: 2015

Myopia incidence in China is rapidly becoming a very serious sight compromising problem in a large segment of the general population. Therefore, delineating the underlying mechanisms leading to myopia will markedly lessen the likelihood of other sight compromising complications. In this regard, there is some evidence that patients afflicted with familial adenomatous polyposis (FAP), havean adenomatous polyposis coli (APC) mutation and a higher incidence of myopia. To clarify this possible association, we determined whether the changes in pertinent biometric and biochemical parameters underlying postnatal refractive error development in APCMin mice are relevant for gaining insight into the pathogenesis of this disease in humans. The refraction and biometrics in APCMin mice and age-matched wild-type (WT) littermates between postnatal days P28 and P84 were examined with eccentric infrared photorefraction (EIR) and customized optical coherence tomography (OCT). Compared with WT littermates, the APCMin mutated mice developed myopia (average-4.64 D) on P84 which was associated with increased vitreous chamber depth (VCD). Furthermore, retinal and scleral changes appear in these mice along with: 1) axial length shortening; 2) increased retinal cell proliferation; 3) and decreased tyrosine hydroxylase (TH) expression, the rate-limiting enzyme of DA synthesis. Scleral collagen fibril diameters became heterogeneous and irregularly organized in the APCMin mice. Western blot analysis showed that scleral alpha-1 type I collagen (col1á1) expression also decreased whereas MMP2 and MMP9 mRNA expression was invariant. These results indicate that defective APC gene function promotes refractive error development. By characterizing in APCMin mice ocular developmental changes, this approach provides novel insight into underlying pathophysiological mechanisms contributing to human myopia development. © 2015 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Cai J.,Wenzhou University | Cai J.,State Key Laboratory Cultivation Base and Key Laboratory of Vision Science | Cai J.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry | Yin G.,Wenzhou University | And 24 more authors.
Journal of Neuroinflammation | Year: 2014

Background: Previous reports have indicated that matrix metallopeptidase-2 (MMP-2) regulates angiogenic processes, which are involved in choroidal neovascularization (CNV). However, the regulation of MMP-2 in CNV has not been well-characterized. To gain more information about the regulation of MMP-2 in CNV, we analyzed the circuitry associated with MMP-2 regulation in a CNV model and in cell cultures, focusing on NFκB and the microRNA-29 family (miR-29s).Methods: The CNV model was established by subjecting C57BL/6 mice to fundus photocoagulation with a krypton red laser. In choroidal-retinal pigment epithelial (RPE) tissues of the model, immunohistochemistry was used to evaluate the angiogenesis and MMP-2 expression; reverse-transcription quantitative PCR (RT-qPCR) was used to determine the levels of miR-29s; and western blot was used to analyze the protein levels of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) inhibitor, IκBα, and its phosphorylated form, phospho-IκBα. At the cellular level, RT-qPCR was used to examine the levels of miR-29s following NFκB activation by tumor necrosis factor alpha (TNFα); and western blot and luciferase assay were used to determine the regulation of MMP-2 by miR-29s in a human RPE cell line (ARPE-19) and in an umbilical vein endothelial cell line (EA hy926).Results: MMP-2 staining was increased in the choroidal neovascular membrane of laser-treated retina. Also, the NFκB pathway was induced in choroid-RPE tissue, as evidenced by a lower protein level of IκBα and a higher level of phospho-IκBα in the tissue homogenates than in those from non-treated eyes. During the period when the NFκB pathway was induced, reduced miR-29s were detected in the choroidal-RPE tissue of the laser-treated eyes. In cultured ARPE-19 cells, TNFα decreased miR-29a, b, and c, and the effects were rescued by NFκB decoy. In ARPE-19 and EA hy926, miR-29s mimics reduced the contents of secreted MMP-2 in the culture media. We also documented that miR-29s reduced MMP-2 3'-UTR-mediated luciferase transcription.Conclusions: The results suggest that in CNV, NFκB activation inhibits miR-29s, which may contribute to angiogenesis by up-regulating the MMP-2 protein level in RPE cells. These observations may help in developing a strategy for resolving CNV by targeting miR-29s levels. © 2014 Cai et al.; licensee BioMed Central Ltd.


Zhou X.,Wenzhou Medical College | Zhou X.,State Key Laboratory Cultivation Base | Zhou X.,Key Laboratory of Vision Science | Zhou X.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry | And 30 more authors.
Investigative Ophthalmology and Visual Science | Year: 2010

PURPOSE. To critically evaluate whether the adenosine A2A receptor (A2AR) plays a role in postnatal refractive development in mice. METHODS. Custom-built biometric systems specifically designed for mice were used to assess the development of relative myopia by examining refraction and biometrics in A2AR knockout (KO) mice and wild-type (WT) littermates between postnatal days (P)28 and P56. Ocular dimensions were measured by customized optical coherence tomography (OCT), refractive state by eccentric infrared photorefraction (EIR), and corneal radius of curvature by modified keratometry. Scleral collagen diameter and density were examined by electron microscopy on P35. The effect of A2AR activation on collagen mRNA expression and on soluble collagen production was examined in cultured human scleral fibroblasts by real-time RT-PCR and a collagen assay kit. RESULTS. Compared with WT littermates, the A2AR KO mice displayed relative myopia (average difference, 5.1 D between P28 and P35) and associated increases in VC depth and axial length from P28 to P56. Furthermore, the myopic shift in A2AR KO mice was associated with ultrastructural changes in the sclera: Electron microscopy revealed denser collagen fibrils with reduced diameter in A2AR KO compared with WT. Last, A2AR activation induced expression of mRNAs for collagens I, III, and V and increased production of soluble collagen in cultured human scleral fibroblasts. © Association for Research in Vision and Ophthalmology.


Dong F.,Wenzhou Medical College | Dong F.,State Key Laboratory Cultivation Base | Dong F.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry | Zhi Z.,Wenzhou Medical College | And 28 more authors.
Molecular Vision | Year: 2011

Purpose: The dopamine (DA) system in the retina is critical to normal visual development as lack of retinal DA signaling may contribute to myopic development. The involvement of DA in myopic development is complex and may be different between form deprivation and hyperopic defocus. This study evaluated effects of a non-selective DA receptor agonist, apomorphine (APO) on refractive development in guinea pigs treated with form deprivation or hyperopic defocus. Methods: APO was subconjunctivally injected daily for 11 days in form-deprived (0.025 to 2.5 ng/μl) and defocused (0.025 to 250 ng/μl) eyes. Changes in ocular biometry and retinal concentration of DA and its metabolites (DOPAC) were measured in the 2 animal models to assess the level of DA involvement in each of the models (the less the change, the lower the involvement). Results: Similar myopic degree was induced in both the deprived and defocused eyes (-4.06 D versus -3.64 D) at 11 days of the experiment. DA and DOPAC levels were reduced in the deprived eyes but did not change significantly in the defocused eyes compared to the fellow and normal control eyes. A subconjunctival injection of APO daily for 11 days at concentrations ranged from 0.025 to 2.5 ng/μl inhibited form deprivation myopia in a concentration-dependent manner. By contrast, the APO treatment ranged from 0.025 to 250 ng/μl did not effectively inhibit the defocus-induced myopia and the associated axial elongation. Conclusions: DA signaling may play a more critical role in form deprivation myopia than in defocus-induced myopia, raising a question whether the mechanisms of DA signaling are different under these two types of experimental myopia. © 2011 Molecular Vision.


Jiang Z.,Wenzhou Medical College | Jiang Z.,State Key Laboratory Cultivation Base | Jiang Z.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry | Shen M.,Wenzhou Medical College | And 15 more authors.
Eye | Year: 2011

To examine the relationship between corneal biomechanical properties and the degree of myopia. Methods Chinese subjects (n=172, age: 11-65 years) were divided into diagnostic groups with non-myopia (spherical equivalence (SE)<-0.50 D), low (-3.00≥SE≥-0.50 D), moderate (-6.00≥SE≥-3.00 D), and high myopia (SE>-6.00 D). Only the right eye of each subject was analyzed. Central corneal thickness (CCT) was measured by optical coherence tomography. An ocular response analyzer was used to measure corneal hysteresis (CH), corneal resistance factor (CRF), intraocular pressure (IOP), and corneal compensated IOP (IOPcc). Refraction was measured by both automated and subjective refractometry and expressed as SE. Results CH was significantly lower in high myopia compared with both low and non-myopia (P≥0.002). CCT was 1.5 times more correlated to CH variation compared with refraction. Similarly, CRF was four times more dependent on CCT than refraction. CH (P>0.001) or CRF (P=0.005) was positively correlated to refraction. Both IOP and IOPcc were negatively correlated to refraction (P>0.001), respectively. Conclusions CH decreases only in high myopia. Refraction is positively correlated to both CH and CRF but negatively correlated to both IOP and IOPcc. These results indicate that the mechanical strength in anterior segment of the eye is compromised in high myopia. In addition, high myopia may increase the risk of glaucoma. © 2011 Macmillan Publishers Limited All rights reserved.


Jiang Z.,Wenzhou Medical College | Jiang Z.,State Key Laboratory Cultivation Base | Jiang Z.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry | Shen M.,Wenzhou Medical College | And 14 more authors.
Eye and Contact Lens | Year: 2013

PURPOSE:: To investigate the changes in axial length and retinal thickness and their relationships with myopia in highly myopic anisometropia. METHODS:: A total of 87 Chinese subjects (25.28±11.98 years, mean±SD) were divided into two groups: anisometropia (n=38) and nonanisometropia (n=49). All eyes were measured for axial length, refractive status, and macular thickness (optical coherence tomography). Ocular biometric results were compared between eyes of subgroups. Linear correlation between refractive error and other biometric results was performed. RESULTS:: In the anisometropic group, the inner ring macula and part of the outer ring macula (nasal and inferior quadrants) in the higher myopic eyes were significantly thinner than in the fellow eyes (P≤0.007), but the foveal thickness (minimum and average) was similar (P≥0.050) between the two eyes. However, the minimum and average foveal thicknesses were found to be significantly thicker in the highly myopic eyes than those in the emmetropic to moderate myopic eyes (P≤0.016) in the nonanisometropic group. Among the eyes ranging from emmetropia to high myopia, the refractive error was negatively correlated to the axial length of the eye (P<0.001) and the thinning of inner ring macula is consistent with the increase in both myopia and axial length. There was a negative correlation in refractive error and axial length but no correlation in parafoveal thickness between eyes of the same subjects (P<0.001) in the anisometropic group. CONCLUSIONS:: In people with myopic anisometropia, the higher myopic eye has a longer axial length but a thinner parafoveal region than its fellow eye. The axial growth in the development of high myopia seems to be centrally regulated; however, the changes in parafoveal thickness are likely manipulated by local mechanisms within the eye. © 2013 Contact Lens Association of Ophthalmologists.


Ding Y.,Wenzhou Medical College | Ding Y.,State Key Laboratory Cultivation Base | Ding Y.,Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry | Chen X.,Wenzhou Medical College | And 15 more authors.
Molecular Vision | Year: 2010

Purpose: High myopia or pathological myopia is a common refractive error. Individuals with high myopia are subject to increased risk of serious eye complications. Accumulating evidence has demonstrated the role for heritability in ocular growth and in the development of high myopia. Retinoic acid and retinoic acid receptors play important roles in ocular development and in experimentally induced myopia. The purpose of this study was to determine if high myopia is associated with single nucleotide polymorphism (SNP) variants in the retinoic acid receptor beta (RARβ) gene in Chinese subjects. Methods: DNA samples were purified from venous lymphocytes of 175 unrelated Chinese patients with high myopia (less than -8.00 diopters) and 101 Chinese control subjects without high myopia (±1.00 diopters). Direct nucleotide sequence analysis in the RARβ gene was performed, and the detected variations were further confirmed by reverse sequencing. Allelic frequencies of all detected SNPs were assessed for Hardy-Weinberg equilibrium. Results: Five variations in RARβ were detected in Chinese subjects with high myopia, including 32574G>A, 32629G>A, 32645C>T, 32647T>G, and 151973C>T, of which only 32647T>G (NCBI notes as rs58244688 and rs2067964) had already been reported. The majority of SNP genotypes were heterozygous. While 32647T>G, 32629G>A, and 32645C>T were located in introns and 32574G>A and 151973C>T were located in coding regions, none of the SNPs affected the amino acid sequence. In the present study, no evidence of association was found between variations in the nucleotide sequence of RARβ and high myopia. Conclusions: Five SNP variants in RARβ were detected in Chinese subjects with high myopia, none of them were associated significantly with high myopia. Further studies are needed to identify which genes are responsible for high myopia. © 2010 Molecular Vision.

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