Keratinocyte Migration in the Developing Eyelid Requires LIMK2

Rice, Dennis S.; Hansen, Gwenn M.; Liu, Feng; Crist, Mike J.; Newhouse, Matthew M.; Potter, David; Xu, Nanfei; Abuin, Alejandro; Vogel, Peter; Zambrowicz, Brian

doi:10.1371/journal.pone.0047168

Cited by 20 publications

(18 citation statements)

References 45 publications

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“…Substantiating evidence comes from genetic studies, which show essential roles for Rho-associated kinases 1 and 2 (ROCKs 1 and 2) and their relative, LIMK2 (Shimizu et al, 2005; Thumkeo et al, 2005; Rice DS et al, 2012). Further strengthening the notion that actomyosin bundle formation is essential for eyelid closure is that EGF cannot stimulate myosin light chain (MLC) phosphorylation when ROCK1 is absent (Shimizu et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Further strengthening the notion that actomyosin bundle formation is essential for eyelid closure is that EGF cannot stimulate myosin light chain (MLC) phosphorylation when ROCK1 is absent (Shimizu et al, 2005). Moreover, LIMK2-deficient keratinocytes in vitro show reduced actin filaments (Rice DS et al, 2012). Together, these results have led to the hypothesis that eyelid closure might be analogous to wound healing in mammals and/or dorsal closure in Drosophila, and driven either by a) constriction of a supracellular actin cable at the epidermal border in a mode of purse-string closure, and/or b) forward migration of a growing epithelial sheet across the cornea.…”

Section: Discussionmentioning

confidence: 99%

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Forces Generated by Cell Intercalation Tow Epidermal Sheets in Mammalian Tissue Morphogenesis

et al. 2014

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Summary While gastrulation movements offer mechanistic paradigms for how collective cellular movements shape developing embryos, far less is known about coordinated cellular movements that occur later in development. Studying eyelid closure, we explore a case where an epithelium locally reshapes, expands, and moves over another epithelium. Live imaging, gene targeting and cell cycle inhibitors reveal that closure does not require overlying periderm, proliferation or supracellular actin cable assembly. Laser ablation and quantitative analyses of tissue deformations further distinguish the mechanism from wound-repair and dorsal closure. Rather, cell intercalations parallel to the tissue front locally compress it perpendicularly, pulling the surrounding epidermis along the closure axis. Functional analyses in vivo show that the mechanism requires localized myosin-IIA and α5β1-fibronectin-mediated migration, and E-cadherin downregulation likely stimulated by Wnt signaling. These studies uncover a mode of epithelial closure in which forces generated by cell intercalation are leveraged to tow the surrounding tissue.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Forces Generated by Cell Intercalation Tow Epidermal Sheets in Mammalian Tissue Morphogenesis

et al. 2014

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“…The wild type C57/BL6 strain was from Jackson Laboratory, and the genetic mutant strains, carrying mutations in c-Jun, Limk2, Map3k1, Jnk1, S1pr2/S1pr3 , were as described [20–24]. The c-Jun( Δ OSE) mice were derived from crossing c-Jun-floxed with Le-cre transgenetic strain, in which the Cre recombinase was expressed specifically in the ocular surface ectoderm (OSE) [25].…”

Section: Methodsmentioning

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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“…Mammalian LIMK1 is required for synaptic architecture, 78 while knocking out LIMK2 results in an eyelid defect in mice. 79 Recently an adaptor LRAP25 has been described which links MRCK to LIMK1 46 in a similar way to LRAP35 coupling MRCK with MYO18a. The lamellipodium-localized LRAP25-MRCK complex allows activation of LIMK1, which promotes Factin stability and allows membrane protrusion.…”

Section: Mrck Substratesmentioning

confidence: 99%

Myotonic dystrophy kinase-related Cdc42-binding kinases (MRCK), the ROCK-like effectors of Cdc42 and Rac1

Zhao

Manser

2015

Small GTPases

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Cdc42 is a member of the Rho GTPase protein family that plays key roles in local F-actin organization through a number of kinase and non-kinase effector proteins. The myotonic dystrophy kinase-related Cdc42-binding kinases (MRCKs), and the RhoA binding coiled-coil containing kinases (ROCKs) are widely expressed members of the Dystrophia myotonica protein kinase (DMPK) family. The MRCK proteins are ∼190 kDa multi-domain proteins expressed in all cells and coordinate certain acto-myosin networks. Notably MRCK is a key regulator of myosin18A and myosin IIA/B, and through phosphorylation of their common regulatory light chains (MYL9 or MLC2) to promote actin stress fiber contractility. The MRCK kinases are regulated by Cdc42, which is required for cell polarity and directional migration; MRCK links to the acto-myosin complex through interaction with a coiled-coil containing adaptor proteins LRAP35a/b. The biological activities of MRCK in model organisms such as worms and flies confirm it as a myosin II activator. In mammalian cell culture MRCK can be critical for cancer cell migration and neurite outgrowth. We review the current literatures regarding MRCK and highlight the similarities and differences between MRCK and ROCK kinases.

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Keratinocyte Migration in the Developing Eyelid Requires LIMK2

Cited by 20 publications

References 45 publications

Forces Generated by Cell Intercalation Tow Epidermal Sheets in Mammalian Tissue Morphogenesis

Forces Generated by Cell Intercalation Tow Epidermal Sheets in Mammalian Tissue Morphogenesis

Meibomian gland morphogenesis requires developmental eyelid closure and lid fusion

Myotonic dystrophy kinase-related Cdc42-binding kinases (MRCK), the ROCK-like effectors of Cdc42 and Rac1

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