Patterning the Vertebrate Retina with Morphogenetic Signaling Pathways

Cardozo, Marcos J.; Almuedo-Castillo, María; Bovolenta, Paola

doi:10.1177/1073858419874016

Cited by 23 publications

(26 citation statements)

References 73 publications

(100 reference statements)

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“…Eye identity is established in the anterior neural plate by the early activation of a gene regulatory network (GRN) pivoting on a few key regulators collectively known as eye field transcription factors (EFTF): including Lhx2,Otx2,Pax6,Rx,or Six3 (Zuber, et al, 2003). Upon the influence of inductive signals derived from the lens epithelium (FGFs) or the extraocular mesenchyme (Wnts and BMPs), the eye field network branches into the mutually exclusive developmental programs of the NR and RPE (Cardozo, et al, 2020;Fuhrmann, 2010). Classical genetic experiments performed mainly in mice have identified key nodes of the NR and RPE specification networks.…”

Section: Introductionmentioning

confidence: 99%

Analysis of gene network bifurcation during optic cup morphogenesis in zebrafish

Bono

Naranjo

Moreno-Mármol

et al. 2020

Preprint

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SummarySight depends on the tight cooperation between photoreceptors and pigmented cells. Both derive from common progenitors in which a single gene regulatory network (GRN) bifurcates into the neural retina (NR) and retinal-pigmented epithelium (RPE) programs. Although genetic studies have identified upstream nodes controlling these networks, their regulatory logic remains poorly investigated. Here, we characterize transcriptome dynamics (RNA-seq) and chromatin accessibility (ATAC-seq) in segregating NR/RPE populations in zebrafish. Analysis of active cis-regulatory modules and enriched transcription factor (TF) motives suggest extensive network redundancy and context-dependent TF activity. Downstream targets identification highlights an early recruitment of desmosomal genes in the flattening RPE, revealing Tead factors as upstream regulators. Investigation of GRNs dynamics uncovers an unexpected sequence of TF recruitment during RPE specification, which is conserved in humans. This systematic interrogation of the NR/RPE bifurcation should improve both genetic counselling for eye disorders and hiPSCs-to-RPE differentiation protocols for cell-replacement therapies in degenerative diseases.

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Section: Introductionmentioning

confidence: 99%

Analysis of gene network bifurcation during optic cup morphogenesis in zebrafish

Bono

Naranjo

Moreno-Mármol

et al. 2020

Preprint

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“…Under the influence of inductive signals (4,5), the two layers activate different genetic programs that specify the cells of the inner layer and ventral outer layer as NR and those of the dorsal outer layer as RPE (6)(7)(8). Whilst this specification occurs, the OV bends assuming a cup-like shape (9).…”

Section: Introductionmentioning

confidence: 99%

Stretching of the retinal pigment epithelium contributes to zebrafish optic cup morphogenesis

Moreno-Mármol

Ledesma-Terrón

Tabanera

et al. 2020

Preprint

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The vertebrate eye primordium consists of a pseudostratified neuroepithelium, the optic vesicle (OV), in which cells acquire neural retina or retinal pigment epithelium (RPE) fates. As these fates arise, the OV assumes a cup-shape, influenced by mechanical forces generated within the neural retina. Whether the RPE passively adapts to retinal changes or actively contributes to OV morphogenesis remains unexplored. Here, we generated a zebrafish Tg(E1-bhlhe40:GFP) line to track RPE morphogenesis and interrogate its participation in OV folding. We show that, in virtual absence of proliferation, RPE cells stretch into a squamous configuration, thereby matching the curvature of the underlying retina. Forced proliferation and localized interference with the RPE cytoskeleton disrupt its stretching and OV folding. Thus, extreme RPE flattening and accelerated differentiation are efficient solutions adopted by fast-developing species to enable timely optic cup formation. This mechanism differs in amniotes, in which proliferation largely drives RPE expansion with a much-reduced need of cell flattening.

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“…The expression patterns of the pan-ocular paired PAX6 transcription factor (n=3) and retina-specific VSX2 homeodomain transcription factor (n=4) are unchanged in the ventral optic cup of Nf2 CKO embryos at E11.5 (Fig.2B, D). Dorsal localization of the T-box transcription factor TBX5 is unaltered in the Nf2 CKO optic cup ( Fig.2F; n=4, E11.5-E13.5) (85).…”

Section: Loss Of Nf2 Function Leads To a Narrow Coloboma In The Ventrmentioning

confidence: 98%

Nf2 fine-tunes proliferation and tissue alignment during closure of the optic fissure in the embryonic mouse eye

Sun

Ramirez

Spiller

et al. 2020

Preprint

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Uveal coloboma represents one of the most common congenital ocular malformations accounting for up to 10% of childhood blindness (1~ in 5,000 live birth). Coloboma originates from defective fusion of the optic fissure (OF), a transient gap that forms during eye morphogenesis by asymmetric, ventral invagination. Genetic heterogeneity combined with the activity of developmentally regulated genes suggest multiple mechanisms regulating OF closure. The tumor suppressor and FERM domain protein neurofibromin 2 (NF2) controls diverse processes in cancer, development and regeneration, via Hippo pathway and cytoskeleton regulation. In humans, NF2 mutations can cause ocular abnormalities, including coloboma, however, its actual role in OF closure is unknown. Using conditional inactivation in the embryonic mouse eye, our data indicates that loss of Nf2 function results in a novel underlying cause for coloboma. In particular, mutant eyes show substantially increased RPE proliferation in the fissure region with concomitant acquisition of RPE cell fate. Cells lining the OF margin can maintain RPE fate ectopically and fail to transition from neuroepithelial to cuboidal shape. In the dorsal RPE of the optic cup, Nf2 inactivation leads to a robust increase in cell number, with local disorganization of the cytoskeleton components F--actin and pMLC2. We propose that RPE hyperproliferation is the primary cause for the observed defects causing insufficient alignment of the OF margins in Nf2 mutants and failure to fuse properly, resulting in persistent coloboma. Our findings indicate that limiting proliferation particularly in the RPE layer is a critical mechanism during optic fissure closure.

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Patterning the Vertebrate Retina with Morphogenetic Signaling Pathways

Cited by 23 publications

References 73 publications

Analysis of gene network bifurcation during optic cup morphogenesis in zebrafish

Analysis of gene network bifurcation during optic cup morphogenesis in zebrafish

Stretching of the retinal pigment epithelium contributes to zebrafish optic cup morphogenesis

Nf2 fine-tunes proliferation and tissue alignment during closure of the optic fissure in the embryonic mouse eye

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