Phase transition specified by a binary code patterns the vertebrate eye cup

Balasubramanian, Revathi; Min, Xuanyu; Quinn, Peter M J; Giudice, Quentin Lo; Tao, Chenqi; Polanco, Karina; Makrides, Neoklis; Peregrin, John; Bouaziz, Michael; Mao, Yihua; Wang, Qian; Costa, Bruna Lopes da; Buenaventura, Diego F.; Wang, Fen; Ma, Liang; Tsang, Stephen H.; Fabre, Pierre J.; Zhang, Xin

doi:10.1126/sciadv.abj9846

Cited by 25 publications

(25 citation statements)

References 59 publications

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“…We have previously shown that the mammalian CM is specified by a binary code of FGF and Wnt signaling, whose relative balance determine the retinal progenitor cell fate in a phase transition like manner. In support of this model, we and others showed that abrogation of Wnt secretion from the lens or Wnt signaling effector β-catenin in the peripheral retina abolished CM development (Liu et al 2007; Fujimura et al 2009; Westenskow et al 2009; Bharti et al 2012; Balasubramanian et al 2021). Conversely, constitutive activation of β-catenin in the NR induces the ectopic CM (Liu et al 2007; Ha et al 2012).…”

Section: Introductionsupporting

confidence: 59%

Wnt signaling regulates passive cell competition in the retina by inducing differential cell adhesion

Min

Mao

et al. 2022

Preprint

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Self-assortation of progenitor cells during development is essential for establishment of distinct tissue identity. This is exemplified in the eye, where the early optic cup is divided into the neural retina (NR) in the center and the ciliary margin (CM) in the periphery. Previous studies have demonstrated that Wnt signaling is required for specification of the CM, but here we show that genetic ablation of Wnt signaling mediator β-catenin in the peripheral optic cup failed to prevent the formation of the CM-derived ciliary body and iris in adult animals. Mosaic analysis revealed that this was only partially due to loss of adherens junctions among β-catenin deficient cells, which were preferentially excluded from the CM. Even in β-catenin mutant cells that can maintain adherens junctions, their inability to mediate Wnt signaling resulted in a change from P-cadherin to N-cadherin expression. We showed that this cadherin switch was sufficient to segregate otherwise identical cells into separate clusters. As a result, the ciliary body and iris were still formed after inactivation of Wnt signaling in the peripheral retina. These results showed that the dual functions of β-catenin in adherens junction and Wnt signaling are required for the passive cell competition to constitute retinal compartments.

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Section: Introductionsupporting

confidence: 59%

Wnt signaling regulates passive cell competition in the retina by inducing differential cell adhesion

Min

Mao

et al. 2022

Preprint

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“…Retinal endothelial cells also express Arhgef12 transcripts during postnatal angiogenesis in mice at P8 [ 92 ]. From single-cell RNA sequencing online resources (The Broad Institute Single Cell Portal, https://singlecell.broadinstitute.org/single_cell , accessed March 12, 2022), Arhgef12 transcripts were observed in retinal progenitor cells at embryonic day 13.5 [ 93 ] and in amacrine, horizontal, and ganglion cells, astrocytes, fibroblasts, pericytes, and vascular endothelium at P14 [ 94 ], while Prkci transcripts were detected in horizontal cells [ 94 ]. Although these studies support the hypothesis that apicobasal polarity defects in retinal progenitor cells cause retinal dysplasia, the observation that Arhgef12 , Prkci , and Crb1 genes are expressed in retinal endothelial cells raises the intriguing possibility that vascular cell polarity defects may also contribute to the disease.…”

Section: Discussionmentioning

confidence: 99%

Identification of Arhgef12 and Prkci as genetic modifiers of retinal dysplasia in the Crb1rd8 mouse model

et al. 2022

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Mutations in the apicobasal polarity gene CRB1 lead to diverse retinal diseases, such as Leber congenital amaurosis, cone-rod dystrophy, retinitis pigmentosa (with and without Coats-like vasculopathy), foveal retinoschisis, macular dystrophy, and pigmented paravenous chorioretinal atrophy. Limited correlation between disease phenotypes and CRB1 alleles, and evidence that patients sharing the same alleles often present with different disease features, suggest that genetic modifiers contribute to clinical variation. Similarly, the retinal phenotype of mice bearing the Crb1 retinal degeneration 8 (rd8) allele varies with genetic background. Here, we initiated a sensitized chemical mutagenesis screen in B6.Cg-Crb1rd8/Pjn, a strain with a mild clinical presentation, to identify genetic modifiers that cause a more severe disease phenotype. Two models from this screen, Tvrm266 and Tvrm323, exhibited increased retinal dysplasia. Genetic mapping with high-throughput exome and candidate-gene sequencing identified causative mutations in Arhgef12 and Prkci, respectively. Epistasis analysis of both strains indicated that the increased dysplastic phenotype required homozygosity of the Crb1rd8 allele. Retinal dysplastic lesions in Tvrm266 mice were smaller and caused less photoreceptor degeneration than those in Tvrm323 mice, which developed an early, large diffuse lesion phenotype. At one month of age, Müller glia and microglia mislocalization at dysplastic lesions in both modifier strains was similar to that in B6.Cg-Crb1rd8/Pjn mice but photoreceptor cell mislocalization was more extensive. External limiting membrane disruption was comparable in Tvrm266 and B6.Cg-Crb1rd8/Pjn mice but milder in Tvrm323 mice. Immunohistological analysis of mice at postnatal day 0 indicated a normal distribution of mitotic cells in Tvrm266 and Tvrm323 mice, suggesting normal early development. Aberrant electroretinography responses were observed in both models but functional decline was significant only in Tvrm323 mice. These results identify Arhgef12 and Prkci as modifier genes that differentially shape Crb1-associated retinal disease, which may be relevant to understanding clinical variability and underlying disease mechanisms in humans.

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“…Moreover, FGF signalling regulates the activity of Wnt signalling, which is also required for CM development [111]. The synergy between FGF and Wnt signalling is revealed by a gain-of-function experiment, showing that constitutively active Wnt signalling transforms the NR into the CM or the RPE depending on the presence or the absence of FGF signalling, respectively [110]. This finding reveals a binary code of eye cup patterning in which the Wnt+/ FGF− condition biases towards the RPE, Wnt+/FGF+ towards the CM and Wnt−/FGF+ towards the NR.…”

Section: Regional Specification Of the Optic Cupmentioning

confidence: 99%

Jack of all trades, master of each: the diversity of fibroblast growth factor signalling in eye development

et al. 2022

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A central question in development biology is how a limited set of signalling pathways can instruct unlimited diversity of multicellular organisms. In this review, we use three ocular tissues as models of increasing complexity to present the astounding versatility of fibroblast growth factor (FGF) signalling. In the lacrimal gland, we highlight the specificity of FGF signalling in a one-dimensional model of budding morphogenesis. In the lens, we showcase the dynamics of FGF signalling in altering functional outcomes in a two-dimensional space. In the retina, we present the prolific utilization of FGF signalling from three-dimensional development to homeostasis. These examples not only shed light on the cellular basis for the perfection and complexity of ocular development, but also serve as paradigms for the diversity of FGF signalling.

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Phase transition specified by a binary code patterns the vertebrate eye cup

Abstract: FGF and Wnt signaling controls the phase transition of the ocular fate.

Cited by 25 publications

References 59 publications

Wnt signaling regulates passive cell competition in the retina by inducing differential cell adhesion

Wnt signaling regulates passive cell competition in the retina by inducing differential cell adhesion

Identification of Arhgef12 and Prkci as genetic modifiers of retinal dysplasia in the Crb1rd8 mouse model

Jack of all trades, master of each: the diversity of fibroblast growth factor signalling in eye development

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