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Glycosaminoglycans are ubiquitously expressed polysaccharides that are attached to proteoglycans. Here, we showed that ablation of the heparan sulfate (HS) polymerase Ext1 in retinal progenitor cells did not affect initial progression of retinal angiogenesis, but it disrupted the pruning of blood vessels and establishment of arterioles and venules. In the absence of retinal HS, blood vessels were also vulnerable to high oxygen tension in early postnatal stages, which could be rescued by exogenous vascular endothelial growth factor (VEGF), consistent with the role of retinal HS in the fine-tuning of VEGF signaling. Furthermore, we observed that the retinal inner limiting membrane (ILM) was disrupted by deletion of Ext1 in a timing-specific manner, suggesting that retinal HS is required for the assembly but not the maintenance of the basement membrane. Lastly, we showed that further deletion of C4st1, a chondroitin sulfate (CS) sulfation enzyme, did not affect the assembly of the ILM but, when combined with Ext1 deletion, it aggravated the retinal permeability by disrupting the retinal glycocalyx. These results demonstrate an important role of CS and HS in establishing the barrier function of the extracellular matrix.

Description, FGF and Wnt signaling controls the phase transition of the ocular fate., The developing vertebrate eye cup is partitioned into the neural retina (NR), the retinal pigmented epithelium (RPE), and the ciliary margin (CM). By single-cell analysis, we showed that fibroblast growth factor (FGF) signaling regulates the CM in its stem cell–like property of self-renewal, differentiation, and survival, which is balanced by an evolutionarily conserved Wnt signaling gradient. FGF promotes Wnt signaling in the CM by stabilizing β-catenin in a GSK3β-independent manner. While Wnt signaling converts the NR to either the CM or the RPE depending on FGF signaling, FGF transforms the RPE to the NR or CM dependent on Wnt activity. The default fate of the eye cup is the NR, but synergistic FGF and Wnt signaling promotes CM formation both in vivo and in human retinal organoid. Our study reveals that the vertebrate eye develops through phase transition determined by a combinatorial code of FGF and Wnt signaling.

The intracellular PI3K, MAPK, and mTOR network controls morphogenesis by regulating the distribution of cell surface receptors., The patterning of epithelial buds is determined by the underlying signaling network. Here, we study the cross-talk between phosphoinositide 3-kinase (PI3K) and Ras signaling during lacrimal gland budding morphogenesis. Our results show that PI3K is activated by both the p85-mediated insulin-like growth factor (IGF) and Ras-mediated fibroblast growth factor (FGF) signaling. On the other hand, PI3K also promotes extracellular signal–regulated kinase (ERK) signaling via a direct interaction with Ras. Both PI3K and ERK are upstream regulators of mammalian target of rapamycin (mTOR), and, together, they prevent expansion of epidermal growth factor (EGF) receptor expression from the lacrimal gland stalk to the bud region. We further show that this suppression of EGF signaling is necessary for induction of lacrimal gland buds. These results reveal that the interplay between PI3K, mitogen-activated protein kinase, and mTOR mediates the cross-talk among FGF, IGF, and EGF signaling in support of lacrimal gland development.

The mammalian ciliary margin is a part of the developing peripheral neural retina that differentiates into the ciliary body and the iris. Canonical WNT signaling plays a critical role in the specification of the ciliary margin at the peripheral retina in the presence of strong FGF signaling in the central retina. The mechanism of how the boundary between the central retina and the ciliary margin is created has not been previously elucidated. Using genetic ablation and epistasis experiments, we show that loss of FGF signaling gradient in the peripheral retina causes expansion of WNT signaling towards the central retina thereby disrupting the neurogenic boundary and compartmentalization of the ciliary margin. Loss of WNT signaling displays a complimentary effect with expansion of FGF signaling into the ciliary marginal space. Usingin vivoexperiments, we elucidate the FGF signaling cascade involved in development of the ciliary margin. We also identify the surface ectoderm as the source of WNT ligands in eliciting WNT response at the ciliary margin. We show that an interaction between FGF and WNT signaling is required for generation of the ciliary marginal cells. Taken together, our results reveal that a gradient intersection of FGF and WNT signaling is required for specification of the ciliary margin.

Astrocytes represent the earliest glial population in the embryonic optic nerve, contributing critically to retinal angiogenesis and formation of brain-retinal-barrier (BRB). Despite of many developmental and clinical implications of astrocytes, answers to some of the most fundamental questions of this unique type of glial cells remain elusive. This review provides an overview of the current knowledge about the origination, proliferation and differentiation of astrocytes, their journey from the optic nerve towards the neuroretina, and their involvement in physiological and pathological development of the visual system.

FGF signaling plays a pivotal role in eye development. Previous studies using in vitro chick models and systemic zebrafish mutants have suggested that FGF signaling is required for the patterning and specification of the optic vesicle, but due to a lack of genetic models, its role in mammalian retinal development remains elusive. In this study, we show that specific deletion of Fgfr1 and Fgfr2 in the optic vesicle disrupts ERK signaling, which results in optic disc and nerve dysgenesis and, ultimately, ocular coloboma. Defective FGF signaling does not abrogate Shh or BMP signaling, nor does it affect axial patterning of the optic vesicle. Instead, FGF signaling regulates Mitf and Pax2 in coordinating the closure of the optic fissure and optic disc specification, which is necessary for the outgrowth of the optic nerve. Genetic evidence further supports that the formation of an Frs2α-Shp2 complex and its recruitment to FGF receptors are crucial for downstream ERK signaling in this process, whereas constitutively active Ras signaling can rescue ocular coloboma in the FGF signaling mutants. Our results thus reveal a previously unappreciated role of FGF-Frs2α-Shp2-Ras-ERK signaling axis in preventing ocular coloboma. These findings suggest that components of FGF signaling pathway may be novel targets in the diagnosis of and the therapeutic interventions for congenital ocular anomalies.