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Role of MAP3K1 in Ocular Surface Development

Meng, Qinghang
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406901599

Abstract Details

2014, PhD, University of Cincinnati, Medicine: Toxicology (Environmental Health).
Mammalian eye development requires fusion of the upper and lower eyelids in embryogenesis. Many genetic mutations cause defective eyelid closure in mouse embryogenesis, resulting in an eye open at birth (EOB) phenotype. Previous work from our laboratory has shown that loss function mutation of the gene coding for Mitogen-Activated Protein Kinase Kinase Kinase 1 (MAP3K1) leads to the EOB phenotype. This thesis explores the genetic and gene-environmental interaction mechanisms of MAP3K1 in eyelid closure and the etiology and pathogenesis of congenital diseases associated with defective eyelid closure.

We have shown that MAP3K1 crosstalks with the EGFR and RhoA-ROCK pathways and regulates the Jun N-terminal kinases (JNKs) for lid closure. The transcription factor c-Jun, a JNK substrate, is also essential for eyelid closure, but whether c-Jun is a component of the MAP3K1 signaling network is not known. In Chapter 2, I show that MAP3K1 is associated with cytoskeleton, activates JNK and induces actin polymerization. MAP3K1 promotes the eyelid inferior epithelial cell elongation that leads to the formation of an epithelium protrusion. The c-Jun, on the other hand, is expressed only in the protruding eyelid epithelium, where it promotes ERK phosphorylation and cell migration. Homozygous deletion of either gene results in defective eyelid closure, but the Map3k1 and c-Jun double heterozygous does not. Hence, MAP3K1 and c-Jun belong to distinct pathways, acting consecutively to regulate eyelid morphogenetic closure.

Although genetic codes are the blueprints for organogenesis, environmental insults can modify the developmental programs. Gene-environment interaction is responsible for the majority cases of multifactorial birth defects. In Chapter 3, I show that gene (Map3k1)-environment {2,3,7,8-tetrachlorodibenzodioxin (TCDD)} interaction is an etiology for defective eyelid closure. In utero TCDD exposure causes defective eyelid closure only when the Map3k1 gene is reduced by 50%, and in a manner dependent on the aryl hydrocarbon receptor (AHR). How TCDD-AHR and MAP3K1 axis crosstalk in eyelid morphogenesis is yet to be understood, but likely involves the inhibition of the JNK-c-Jun pathways.

Many genetic mutant mice exhibit the EOB phenotype, but the developmental roles of eyelid closure are not known. In Chapter 4, I examine seven EOB strains, which were generated by different strategies of gene ablation that inactivated distinct signaling pathways. Results show that defective eyelid closure leads to corneal erosion/ulceration, Meibomian gland hypoplasia, truncation of the eyelid tarsal muscles, failure of levator palpebrae superiors (LPS) extension into the upper eyelid and the misplacement of the inferior oblique (IO) and inferior rectus (IR) muscles. Some of the abnormalities can be traced to pre-natal fetuses. Hence, in addition to serving as a protective barrier of the cornea, eyelid closure in embryogenesis is required for the development of ocular adnexa.

Collectively, my results suggest that (1) eyelid closure is regulated by diverse genes acting through temporal-spatial signaling pathways, (2) gene-environment interaction is likely a real life etiology for causing the eyelid closure defects, and (3) the failure of eyelid closure leads to aberrant development of ocular surface and adnexa, which may account for congenital diseases, such as blepharoptosis and strabismus.

Ying Xia, Ph.D. (Committee Chair)
Zubair M. Ahmed, Ph.D. (Committee Member)
Aimin Chen, Ph.D. (Committee Member)
Chia-Yang Liu, Ph.D. (Committee Member)
Alvaro Puga, Ph.D. (Committee Member)
149 p.
Developmental Biology
embryonic eyelid closure; MAP3K1; c-Jun; TCDD; tarsal muscles; extraocular muscles

Recommended Citations

Citations

  • Meng, Q. (2014). Role of MAP3K1 in Ocular Surface Development [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406901599

    APA Style (7th edition)

  • Meng, Qinghang. Role of MAP3K1 in Ocular Surface Development. 2014. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406901599.

    MLA Style (8th edition)

  • Meng, Qinghang. "Role of MAP3K1 in Ocular Surface Development." Doctoral dissertation, University of Cincinnati, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406901599

    Chicago Manual of Style (17th edition)

ucin1406901599
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This open access ETD is published by University of Cincinnati and OhioLINK.