Gene-Environment Interactions Target Mitogen-activated Protein 3 Kinase 1 (MAP3K1) Signaling in Eyelid Morphogenesis

Mongan, Maureen; Meng, Qingxi; Wang, Jingjing; Kao, Winston W.‐Y.; Puga, Alvaro; Xia, Ying

doi:10.1074/jbc.m115.665729

Cited by 10 publications

(13 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the susceptible genetic conditions, such as Map3k1(+/−) and RhoA(−/−) , do not cause eyelid abnormalities by themselves, they potentiate eyelid closure defects in the Jnk1(−/−) mice [26,27,45]. In the present work, we extend the genetic studies to the S1P receptors, S1PR2 and S1PR3, and identify them as additional players of the same pathway.…”

Section: Discussionmentioning

confidence: 73%

See 1 more Smart Citation

Meibomian gland morphogenesis requires developmental eyelid closure and lid fusion

et al. 2017

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 73%

“…In the past few years, EOB mice have become valuable tools for the investigation of molecular and signaling mechanisms of epithelium morphogenesis and for the identification of genetic and environmental risks of developmental diseases [19,28,35,45]. …”

Section: Discussionmentioning

confidence: 99%

Meibomian gland morphogenesis requires developmental eyelid closure and lid fusion

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Detailed molecular analyses have revealed that MAP3K1 acts as a nexus integrating multiple developmental signals, such as Activin B and EGF, and connecting the RhoA and JNK signaling pathways (Geh et al, 2011; Meng et al, 2014b; Takatori et al, 2008; Zhang et al, 2003). Recently, MAP3K1 has been shown to also integrate signals derived from environmental toxic agents (Mongan et al, 2015). Dioxin-like environmental pollutants synergize with Map3k1 allelic mutation to inhibit the JNK pathway and block eyelid closure.…”

Section: Introductionmentioning

confidence: 99%

Repression of MAP3K1 expression and JNK activity by canonical Wnt signaling

Meng

Mongan

Wang

et al. 2018

Developmental Biology

Self Cite

View full text Add to dashboard Cite

Morphogenesis is a complex and highly coordinated process orchestrated by temporal spatial activity of developmental pathways. How the different pathways interact to guide the developmental program remains an intriguing and open question. MAP3K1-JNK and Wnt are signaling pathways crucial for embryonic eyelid closure, an epithelial morphogenetic event conserved in mammals. Here we used a mouse model of eyelid development and genetic and biochemistry tools to investigate the relationships between the two pathways. We found that Wnt activation repressed MAP3K1 expression. Using Axin-LacZ reporter mice, spatial Wnt activity was detected in the leading edge of the developing eyelid. Conditional knockout of Wntless (Wls) in ocular surface ectoderm blocked eyelid formation, and significantly increased MAP3K1 expression in eyelid cells at the nasal canthus region. Conversely, knockout of Dkk2, encoding a canonical Wnt antagonist, resulted in an increase of Wnt activity in cells at the upper eyelid margin near the nasal canthus. Up-regulation of Wnt signaling in the Dkk2-knockout embryos corresponded to down-regulation of MAP3K1 expression. In vitro data showed that Wnt3a treatment decreased MAP3K1 promoter activity, whereas activation of Wnt by lithium chloride inhibited MAP3K1 expression, and attenuated MAP3K1-mediated JNK activity. Our data identify a unique signal crosstalk between Wnt signaling and the MAP3K1-JNK pathway in epithelial morphogenesis.

show abstract

“…Data presented here suggest that abnormalities associated with defective eyelid closure could have polygenic etiology involving a combination of different genetic variants. Additionally, in utero exposure of the environmental toxicant dioxin induced the EOB phenotype in the Map3k1 +/ΔKD but not wild type pups, presenting a case where the eye defects were the result of gene-environment interactions and multifactorial etiology (95). It is thus reasonable to surmise that inactivation of the S1P-MAP3K1-JNK pathways is a molecular mechanism through which genetic and environmental factors induce defective eyelid closure and related developmental disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Wild type and Map3k1 ΔKD mice were backcrossed with BL6 mice for at least 10 generations, as described before (13,95). The Map3k1 ΔKD/ΔKD pups displayed the EOB phenotype and their genotypes were confirmed by established PCR methods.…”

Section: Experimental Animalsmentioning

confidence: 99%

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

Wang

Mongan

Chun

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Gene-Environment Interactions Target Mitogen-activated Protein 3 Kinase 1 (MAP3K1) Signaling in Eyelid Morphogenesis

Cited by 10 publications

References 58 publications

Meibomian gland morphogenesis requires developmental eyelid closure and lid fusion

Meibomian gland morphogenesis requires developmental eyelid closure and lid fusion

Repression of MAP3K1 expression and JNK activity by canonical Wnt signaling

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

Contact Info

Product

Resources

About