Talk:Integumentary System - Eyelid Development

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Cite this page: Hill, M.A. (2019, September 22) Embryology Integumentary System - Eyelid Development. Retrieved from


Molecular biology and genetics of embryonic eyelid development

Ophthalmic Genet. 2016 Sep;37(3):252-9. doi: 10.3109/13816810.2015.1071409. Epub 2016 Feb 11.

Rubinstein TJ1, Weber AC1, Traboulsi EI1.


The embryology of the eyelid is a complex process that includes interactions between the surface ectoderm and mesenchymal tissues. In the mouse and human, the eyelids form and fuse before birth; they open prenatally in the human and postnatally in the mouse. In the mouse, cell migration is stimulated by different growth factors such as FGF10, TGF-α, Activin B, and HB-EGF. These growth factors modulate downstream BMP4 signaling, the ERK cascade, and JNK/c-JUN. Several mechanisms, such as the Wnt/β-catenin signaling pathway, may inhibit and regulate eyelid fusion. Eyelid opening, on the other hand, is driven by the BMP/Smad signaling system. Several human genetic disorders result from dysregulation of the above molecular pathways. KEYWORDS: Embryology; epithelium; eyelid; genetics

PMID 26863902

Embryologic and Fetal Development of the Human Eyelid

Ophthalmic Plast Reconstr Surg. 2016 Nov/Dec;32(6):407-414.

Tawfik HA1, Abdulhafez MH, Fouad YA, Dutton JJ.


PURPOSE: To review the recent data about eyelid morphogenesis, and outline a timeline for eyelid development from the very early stages during embryonic life till final maturation of the eyelid late in fetal life. METHODS: The authors extensively review major studies detailing human embryologic and fetal eyelid morphogenesis. These studies span almost a century and include some more recent cadaver studies. Numerous studies in the murine model have helped to better understand the molecular signals that govern eyelid embryogenesis. The authors summarize the current findings in molecular biology, and highlight the most significant studies in mice regarding the multiple and interacting signaling pathways involved in regulating normal eyelid morphogenesis. RESULTS: Eyelid morphogenesis involves a succession of subtle yet strictly regulated morphogenetic episodes of tissue folding, proliferation, contraction, and even migration, which may occur simultaneously or in succession. CONCLUSIONS: Understanding the extraordinary process of building eyelid tissue in embryonic life, and deciphering its underlying signaling machinery has far reaching clinical implications beyond understanding the developmental abnormalities involving the eyelids, and may pave the way for achieving scar-reducing therapies in adult mammalian wounds, or control the spread of malignancies. PMID: 27124372 PMCID: PMC5102278 DOI: 10.1097/IOP.0000000000000702


Eyelid closure in embryogenesis is required for ocular adnexa development

Invest Ophthalmol Vis Sci. 2014 Nov 6;55(11):7652-61. doi: 10.1167/iovs.14-15155.

Meng Q1, Mongan M1, Carreira V1, Kurita H1, Liu CY2, Kao WW2, Xia Y3.


PURPOSE: Mammalian eye development requires temporary fusion of the upper and lower eyelids in embryogenesis. Failure of lid closure in mice leads to an eye open at birth (EOB) phenotype. Many genetic mutant strains develop this phenotype and studies of the mutants lead to a better understanding of the signaling mechanisms of morphogenesis. The present study investigates the roles of lid closure in eye development. METHODS: Seven mutant mouse strains were generated by different gene ablation strategies that inactivated distinct signaling pathways. These mice, including systemic ablation of Map3k1 and Dkk2, ocular surface epithelium (OSE) knockout of c-Jun and Egfr, conditional knockout of Shp2 in stratified epithelium (SE), as well as the Map3k1/Jnk1 and Map3k1/Rhoa compound mutants, all exhibited defective eyelid closure. The embryonic and postnatal eyes in these mice were characterized by histology and immunohistochemistry. RESULTS: Some eye abnormalities, such as smaller lens in the Map3k1-null mice and Harderian gland hypoplasia in the Dkk2-null mice, appeared to be mutant strain-specific, whereas other abnormalities were seen in all mutants examined. The common defects included corneal erosion/ulceration, meibomian gland hypoplasia, truncation of the eyelid tarsal muscles, failure of levator palpebrae superioris (LPS) extension into the upper eyelid and misplacement of the inferior oblique (IO) muscle and inferior rectus (IR) muscle. The muscle defects were traced to the prenatal fetuses. CONCLUSIONS: In addition to providing a protective barrier for the ocular surface, eyelid closure in embryogenesis is required for the development of ocular adnexa, including eyelid and extraocular muscles. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc. KEYWORDS: LPS; embryonic eyelid closure; extraocular muscles; ocular adnexa; tarsal muscles

PMID 25377219


GPR48 regulates epithelial cell proliferation and migration by activating EGFR during eyelid development

Invest Ophthalmol Vis Sci. 2008 Oct;49(10):4245-53. Epub 2008 May 16.

Jin C, Yin F, Lin M, Li H, Wang Z, Weng J, Liu M, Da Dong X, Qu J, Tu L.

School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, PR China.

Abstract PURPOSE: Eyelid development is a dynamic process involving cell proliferation, differentiation, and migration regulated by a number of growth factors and cytokines. Mice deficient in the orphan G protein-coupled receptor 48 (GPR48) showed an eye open at birth (EOB) phenotype. In this study, the authors attempted to clarify the role of GPR48 in eyelid development and the molecular mechanisms leading to the EOB phenotype.

METHODS: Phenotypic analysis of the eyelids of Gpr48(-/-) mice was carried out using histology and scanning electron microscopy. GPR48 expression pattern was determined using X-gal staining. In vitro scratch assay was used to determine cell motility defects in Gpr48(-)(/)(-) keratinocytes. The molecular mechanism underlying GPR48-mediated eyelid closure was explored using Western blot and immunostaining analyses. Expression levels of EGFR and its phosphorylated counterpart were examined in Gpr48(-/-) and wild-type keratinocytes and in eyelids.

RESULTS: GPR48 is highly expressed in the epithelium and apical mesenchymal cells of eyelids during embryonic development. Detailed analysis revealed that Gpr48(-/-) mice exhibited delayed leading-edge extension, reduced filopodia formation, and decreased rounded periderm cell formation around eyelid margins. Keratinocytes lacking GPR48 are defective in cell proliferation and migration with reduced F-actin staining. In addition, the phosphorylation of EGFR was dramatically decreased in cultured keratinocytes and developing eyelids in the absence of GPR48.

CONCLUSIONS: Inactivation of GPR48 induces the EOB phenotype by reducing epithelial cell proliferation and migration, indicating that GPR48 plays an essential role in eyelid development. Furthermore, GPR48 contributes to eyelid development through the regulation of the EGFR signaling pathway.

PMID 18487371


HB-EGF promotes epithelial cell migration in eyelid development

Development. 2005 Oct;132(19):4317-26. Epub 2005 Sep 1.

Mine N, Iwamoto R, Mekada E.

Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamadaoka, Suita, Osaka 565-0871, Japan.


Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of growth factors that binds to and activates the EGF receptor (EGFR) and ERBB4. Here, we show that HB-EGF-EGFR signaling is involved in eyelid development. HB-EGF expression is restricted to the tip of the leading edge of the migrating epithelium during eyelid closure in late gestation mouse embryos. Both HB-EGF null (HB(del/del)) and secretion-deficient (HB(uc/uc)) mutant embryos exhibited delayed eyelid closure, owing to slower leading edge extension and reduced actin bundle formation in migrating epithelial cells. No changes in cell proliferation were observed in these embryos. In addition, activation of EGFR and ERK was decreased in HB(del/del) eyelids. Crosses between HB(del/del) mice and waved 2 mice, a hypomorphic EGFR mutant strain, indicate that HB-EGF and EGFR interact genetically in eyelid closure. Together with our data showing that embryos treated with an EGFR-specific kinase inhibitor phenocopy HB(del/del) embryos, these data indicate that EGFR mediates HB-EGF-dependent eyelid closure. Finally, analysis of eyelid closure in TGFalpha-null mice and in HB-EGF and TGFalpha double null mice revealed that HB-EGF and TGFalpha contribute equally to and function synergistically in this process. These results indicate that soluble HB-EGF secreted from the tip of the leading edge activates the EGFR and ERK pathway, and that synergy with TGFalpha is required for leading edge extension in epithelial sheet migration during eyelid closure.

PMID 16141218

A dual role of FGF10 in proliferation and coordinated migration of epithelial leading edge cells during mouse eyelid development

Development. 2005 Jul;132(14):3217-30. Epub 2005 Jun 15.

Tao H, Shimizu M, Kusumoto R, Ono K, Noji S, Ohuchi H.

Department of Biological Science and Technology, Faculty of Engineering, University of Tokushima, 2-1 Minami-Jyosanjima, Tokushima 770-8506, Japan.


The development of the eyelid requires coordinated cellular processes of proliferation, cell shape changes, migration and cell death. Mutant mice deficient in the fibroblast growth factor 10 (Fgf10) gene exhibit open-eyelids at birth. To elucidate the roles of FGF10 during eyelid formation, we examined the expression pattern of Fgf10 during eyelid formation and the phenotype of Fgf10-null eyelids in detail. Fgf10 is expressed by mesenchymal cells just beneath the protruding epidermal cells of the nascent eyelid. However, Fgf10-null epithelial cells running though the eyelid groove do not exhibit typical cuboid shape or sufficient proliferation. Furthermore, peridermal clumps are not maintained on the eyelid leading edge, and epithelial extension does not occur. At the cellular level, the accumulation of actin fibers is not observed in the mutant epithelial leading edge. The expression of activin/inhibin betaB (ActbetaB/Inhbb) and transforming growth factor alpha (Tgfa), previously reported to be crucial for eyelid development, is down-regulated in the mutant leading edge, while the onset of sonic hedgehog (Shh) expression is delayed on the mutant eyelid margin. Explant cultures of mouse eyelid primordia shows that the open-eyelid phenotype of the mutant is reduced by exogenous FGF10 protein, and that the expression of ActbetaB and Tgfa is ectopically induced in the thickened eyelid epithelium by the FGF10 protein. These results indicate a dual role of FGF10 in mouse eyelid development, for both proliferation and coordinated migration of eyelid epithelial cells by reorganization of the cytoskeleton, through the regulation of activin, TGFalpha and SHH signaling.

PMID: 15958512


Eyelid development, fusion and subsequent reopening in the mouse

J Anat. 1993 Aug;183 ( Pt 1):121-9.

Findlater GS, McDougall RD, Kaufman MH.

Department of Anatomy, University Medical School, Edinburgh, UK. Abstract The process of eyelid development was studied in the mouse. The critical events occur between about 15.5 d postcoitum (p.c.) and 12 d after birth, and were studied by conventional histology and by scanning electron microscopy. At about 15.5 d p.c. the cornea of the eye is clearly visible with the primitive eyelids being represented by protruding ridges of epithelium at its periphery. Over the next 24 h, eyelid development proceeds to the stage when the cornea is completely covered by the fused eyelids. Periderm cells stream in to fill the gap between the developing eyelids. Their proliferative activity is such that they produce a cellular excrescence on the outer surface of the line of fusion of the eyelids. This excrescence had almost disappeared by about 17.5 d p.c. Keratinisation is first evident at this stage on the surface of the eyelids and passes continuously from one eyelid to the other. Evidence of epidermal differentiation is more clearly seen in the newborn, where a distinctive stratum granulosum now occupies about one third of its entire thickness. Within the subjacent dermis, hair follicles are differentiating. By about 5 d after birth, a thick layer of keratin extends without interruption across the junctional region. While a noticeable surface indentation overlies the latter, a similar depression is only seen on the conjunctival surface by about 10 d after birth. Keratinisation is also observed to extend in from the epidermal surface to involve the entire region between the 2 eyelids at about this time.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 8270467


Eyelid growth and fusion in fetal mice. A scanning electron microscope study

Anat Embryol (Berl). 1982;164(2):207-20.

Harris MJ, McLeod MJ.

Abstract During the last phase of mammalian morphogenesis, between days 14 and 16 of gestation in the mouse, the fetal eyelids grow across the eye and become tightly fused with each other. This paper describes the surface pattern of fetal eyelids, revealed by the scanning electron microscope, during normal eyelid growth and fusion in the ICR/MI stock of mice. Fusion proceeds from both inner and outer canthi and progresses toward the middle of the gap. The first changes in cell shape and distribution occur at the inner canthus. On day 14, a large clump of rounded cells appears on the inner surface of the inner canthus. A day later, two clumps of rounded cells are positioned to either side of, i.e. above and below, the inner canthus. As fusion progresses, the diminishing gap fills with a profusion of rounded cells that are extruded, flattened, and sloughed off from the area of completed fusion. The profusion of rounded surface cells during eyelid growth and fusion appears to be a major characteristic in which the eyelid fusion process differs both from permanent fusions, such as the fusion of the neural tube, lip or palate, and from other temporary fusions, such as fusion of the digits to each other or of the pinnae to the scalp.

PMID 7125235


Genetic background-dependent role of Egr1 for eyelid development

Proc Natl Acad Sci U S A. 2017 Aug 22;114(34):E7131-E7139. doi: 10.1073/pnas.1705848114. Epub 2017 Aug 4.

Oh J1,2, Wang Y3, Chen S3, Li P1,2, Du N1,2, Yu ZX4, Butcher D5, Gebregiorgis T1,2, Strachan E6, Lehmann OJ6, Brooks BP7, Chan CC8, Leonard WJ9,2.


EGR1 is an early growth response zinc finger transcription factor with broad actions, including in differentiation, mitogenesis, tumor suppression, and neuronal plasticity. Here we demonstrate that Egr1-/- mice on the C57BL/6 background have normal eyelid development, but back-crossing to BALB/c background for four or five generations resulted in defective eyelid development by day E15.5, at which time EGR1 was expressed in eyelids of WT mice. Defective eyelid formation correlated with profound ocular anomalies evident by postnatal days 1-4, including severe cryptophthalmos, microphthalmia or anophthalmia, retinal dysplasia, keratitis, corneal neovascularization, cataracts, and calcification. The BALB/c albino phenotype-associated Tyrc tyrosinase mutation appeared to contribute to the phenotype, because crossing the independent Tyrc-2J allele to Egr1-/- C57BL/6 mice also produced ocular abnormalities, albeit less severe than those in Egr1-/- BALB/c mice. Thus EGR1, in a genetic background-dependent manner, plays a critical role in mammalian eyelid development and closure, with subsequent impact on ocular integrity. KEYWORDS: Egr1; eyelid development; genetic background-specific effects; ocular abnormalities; tyrosinase PMID: 28778995