Sphingosine 1-Phosphate Receptors Are Essential Mediators of Eyelid Closure during Embryonic Development

Herr, Deron R.; Lee, Chang-Wook; Wang, Wei; Ware, Adam; Rivera, Richard; Chun, Jerold

doi:10.1074/jbc.m113.510099

Cited by 23 publications

(23 citation statements)

References 61 publications

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“…Recently, the S1P receptors 2 and 3 have been shown to be involved in the regulation of eyelid development [21]. In an attempt to delineate the signaling pathways downstream of S1P receptors, we crossed the receptor mutants with Jnk1 or Map3k1 mutants.…”

Section: Resultsmentioning

confidence: 99%

Meibomian gland morphogenesis requires developmental eyelid closure and lid fusion

et al. 2017

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Background and purpose Meibomian glands (MGs) play an important role in the maintenance of ocular surface health, but the mechanisms of their development are still poorly understood. The MGs arise from the epithelium at the junction of eyelid fusion, raising the possibility that defective eyelid fusion disturbs the formation of MGs. Methods We examined, histologically and functionally, the development of MGs in mice with either normal or defective eyelid fusion, displaying eye-closed at birth (ECB) or eye-open at birth (EOB) phenotypes, respectively. Results The Meibomian anlage was detected in the epithelium at the eyelid fusion junction immediately after birth at postnatal day 0 (PD0), and it extended into the eyelid stroma at PD1 and started to branch and produce meibum at PD7 in the ECB mice. In contrast, few if any MG structures were detectable in the EOB mice in the early postnatal periods. The Meibomian gland ductile system was seen aligned along the eyelid margin in the adult ECB mice, but was absent or scarce in that of the EOB mice. While MG abnormalities were found in all EOB mice, the severity varied and corresponded to the position and the size of eye opening but not the genetic defects of the mice. Conclusion Proper Meibomian gland formation and development require eyelid closure and fusion.

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Section: Resultsmentioning

confidence: 99%

Meibomian gland morphogenesis requires developmental eyelid closure and lid fusion

et al. 2017

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“…Recent genetic data have shown that two of these receptors, S1PR2 and S1PR3, are collectively required for embryonic eyelid closure. Homozygous deletion of the gene encoding either receptor has no apparent effect on eyelid development, but the S1pr2 -/-S1pr3 -/pups are born with an EOB defect (36). While these findings suggest that S1PR2-and S1PR3-mediated signalling are required for eyelid closure, the downstream effector pathways remain elusive.…”

Section: The S1p-map3k1 Pathway In Epithelial Cell Movement and Embrymentioning

confidence: 99%

“…MAP3K1 and S1PR2/S1PR3 are expressed in the same group of epithelial cells in developing eyelids (13,36), leading us to interrogate their relationships in vivo. We crossed the Map3k1 +/ΔKD and the S1pr2/S1pr3 mutant mice and examined the eyelid phenotypes in the newborn pups.…”

Section: The S1p-map3k1 Pathway In Epithelial Cell Movement and Embrymentioning

confidence: 99%

“…S1P is present abundantly in the circulation and specific tissues; it binds to and activates the S1P receptors (S1PRs), which are G protein coupled receptors (GPCRs) that in turn transmit the signals intracellularly to elicit biological responses (31)(32)(33)(34)(35). The S1P/S1PR signal is essential for embryonic eyelid closure, because simultaneous deletion of S1pr2 and S1pr3 genes leads to the EOB phenotype similar to that found in the Map3k1-null pups (36). The relationships between S1P and MAP3K1 signaling in eyelid development, however, are yet to be investigated.…”

Section: Introductionmentioning

confidence: 99%

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Sphingosine 1-phosphate activates the MAP3K1-JNK pathway to promote epithelial movement and morphogenesis

Wang

Mongan

Chun

et al. 2020

Preprint

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MAP 3 kinase 1 (MAP3K1) plays an essential role in embryonic eyelid development. It regulates epithelial morphogenesis through the spatial-temporal activation of Jun N-terminal kinases (JNKs), resulting in forward progression of the embryonic eyelid epithelial cells to enable eyelid closure. The developmental signals that activate the MAP3K1-JNK pathway are still unknown, mainly due to the lack of suitable keratinocyte lines to elucidate the mechanisms of pathway regulation. To address this deficiency, we developed a straightforward method for long-term culture of mouse keratinocytes in feeder-free conditions using Ca2+-free media. Cells grown under these conditions displayed characteristic basal epithelial morphology and keratin 14 expression, but did not form tight- or adherens-junctions. Increased extracellular Ca2+ levels restored the formation of cell-cell junctions. Using keratinocyte lines derived from wild type and Map3k1-deficient mice, we found that sphingosine 1-phosphate (S1P) activated the JNK-c-JUN pathways in a manner dependent on MAP3K1 kinase activity and that this MAP3K1-mediated signaling led to epithelial cell migration. The in vivo roles of this pathway were examined through crossing of genetic mutant mice. Loss-of-function of the S1P receptor (S1pr) 2/3 became haploinsufficient only when combined with Map3k1 and Jnk1 mutations such that the compound mutants displayed eyelid closure defects, suggesting these gene products cooperated in eye morphogenesis. Results of this work establish the S1PR-MAP3K1-JNK pathway as a crucial signaling mechanism for epithelial cell movement and morphogenesis.

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“…Ligand binding to the receptors leads to activation of ERK and induction of epithelial sheet extension. Ablation of S1PR2 and 3 reduces EGF/ERK signaling and delays epithelial sheet extension (Herr et al, 2013). …”

Section: Egfr Signaling In Eyelid Morphogenesismentioning

confidence: 99%

Role of EGF receptor signaling on morphogenesis of eyelid and meibomian glands

Dong

Call

Xia

et al. 2017

Experimental Eye Research

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The epidermal growth factor receptor (EGFR) signaling has a pivotal role in the regulation of morphogenesis during development and maintenance of homeostasis in adult eyelid and its adnexa. Studies have demonstrated that during eyelid morphogenesis the EGFR signaling pathway is responsible for keratinocyte and mesenchymal cell proliferation and migration at the eyelid tip. For meibomian gland morphogenesis, EGFR signaling activation stimulates meibomian gland epithelial cell proliferation. EGFR signaling pathway functions through multiple downstream signals such as ERK, Rho/ROCK and integrin and is regulated by a variety of upstream signals including Adam17, GPR48 and FGFR signaling. Herein we review the literature that describe the role of EGFR and its related signaling pathways in eyelid and meibomian gland morphogenesis.

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Sphingosine 1-Phosphate Receptors Are Essential Mediators of Eyelid Closure during Embryonic Development

Cited by 23 publications

References 61 publications

Meibomian gland morphogenesis requires developmental eyelid closure and lid fusion

Meibomian gland morphogenesis requires developmental eyelid closure and lid fusion

Sphingosine 1-phosphate activates the MAP3K1-JNK pathway to promote epithelial movement and morphogenesis

Role of EGF receptor signaling on morphogenesis of eyelid and meibomian glands

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