Embryologic and Fetal Development of the Eyelid and the Lacrimal Drainage System

Abstract

The embryological and fetal morphogenesis of the eyelids and lacrimal drainage system is multifactorial and complex. This protracted process begins in the 5th week of prenatal life and involves a successive series of subtle and tightly regulated morphogenetic events. Major milestones of the embryological and fetal development of the eyelids include the beginning of eyelid formation during the 6th week, eyelid fusion by the 8th week, and the development of eyelid structures beginning in the 9th week (immediately following eyelid fusion), with progression until eyelid separation by the 24th week. After eyelid separation, the eyelids begin to assume their newly developed shape. Around the 32nd week, eyelids are almost fully developed and fully separated but still visibly closed. Key development steps of the lacrimal drainage system include formation of the lacrimal lamina (the primordium of the future lacrimal system) and the lacrimal cord (the primordium of the lacrimal canaliculi) in the 7th week, with canalization starting from the 10th week. During the 10th week, the excretory lacrimal system displays a lumen with a true lacrimal duct that can be distinguished. The epithelium of the lacrimal canaliculi is in contact with the palpebral conjunctival epithelium. The two epithelia form a continuous epithelial lamina. The caudal extreme of the lacrimal duct and the inferior meatal lamina join and the latter begins to cavitate. Understanding this multidimensional process of development in prenatal life, as well as identifying and linking signaling cascades and regulatory genes to existing diseases, may pave the way for developing minimally invasive interventions and scar reducing surgical methods, controlling the spread of malignancies, and the use of progenitor/stem cell and even regenerative therapy.

Zusammenfassung

Die embryologische und fetale Morphogenese der Augenlider und des Tränendrainagesystems ist multifaktoriell und komplex. Dieser Prozess beginnt in der Regel in der 5. Woche post conceptionem (p. c.) und beinhaltet eine Reihe meist streng regulierter morphogenetischer Entwicklungsschritte. Wichtige Meilensteine der embryologischen und fetalen Entwicklung der Augenlider sind u. a. der Beginn der Augenlidausbildung in der 6. Woche p. c., die Augenlidfusion, die normalerweise bis zur 8. Woche erfolgt, und die Entwicklung der einzelnen Lidstrukturen ab der 9. Woche p. c. Diese schreitet bis zur Lidteilung der 24. Woche p. c. fort. Nach der Augenlidteilung beginnen die Augenlider ihre fast endgültige Form anzunehmen. In der 32. Woche p. c. sind die Augenlider vollständig entwickelt und meistens komplett getrennt, aber noch geschlossen. Zu den wichtigsten Entwicklungsschritten des Tränendrainagesystems gehört: 1. Die Bildung der Lamina lacrimalis (das Primordium des zukünftigen Tränensystems). 2. Die Bildung des Tränenstranges (das Primordium der Tränenkanäle) in der 7. Woche. 3. Die Kanalisation der Tränenwege, die ab der 10. Woche beginnt. In der 10. Woche zeigt das Tränensystem dann ein Lumen mit einem echten Tränengang. Das Epithel der Tränenkanäle geht nun zum palpebralen Bindehautepithel über und das kaudale Ende des Tränenkanals und des Meatus nasalis inferior wachsen zusammen. Das Verständnis für diese Entwicklungsprozesse sowie die Identifizierung und Verknüpfung der Signalkaskaden mit regulatorischen Genen kongenitaler Erkrankungen könnte den Weg für die Entwicklung neuer Therapieoptionen ebnen. Diese könnten minimalinvasive Interventionen und narbenreduzierende Operationsmethoden umfassen. Zudem könnten Therapiemöglichkeiten zur Ausbreitungskontrolle von Malignomen eröffnet werden. Durch die Verwendung von Stammzellen könnten sogar regenerative Therapien in Zukunft möglich sein.

Key words

embryology - morphogenesis - milestones - lacrimal system - anatomic abnormalities

Schlüsselwörter

Embryologie - Morphogenese - Meilensteine - Tränenwegsystem - anatomische Anomalien

Publication History

Received: 23 July 2021

Accepted: 08 December 2021

Article published online:
04 February 2022

• References

• 1 de la Cuadra-Blanco C, Peces-Pena MD, Janez-Escalada L. et al. Morphogenesis of the human excretory lacrimal system. J Anat 2006; 209: 127-135
• 2 Saleh GM, Hussain B, Verity DH. et al. A surgical strategy for the correction of Fraser syndrome cryptophthalmos. Ophthalmology 2009; 116: 1707-1712.e1
• 3 Heindl LM. [Update on minimally invasive lacrimal drainage surgery]. Ophthalmologe 2017; 114: 396
• 4 Rokohl AC, Guo Y, Mor JM. et al. [Intubation Systems in Lacrimal Drainage Surgery – a Current Overview]. Klin Monbl Augenheilkd 2020; 237: 20-28
• 5 Li G, Gustafson-Brown C, Hanks SK. et al. c-Jun is essential for organization of the epidermal leading edge. Dev Cell 2003; 4: 865-877
• 6 Sibilia M, Fleischmann A, Behrens A. et al. The EGF receptor provides an essential survival signal for SOS-dependent skin tumor development. Cell 2000; 102: 211-220
• 7 Zenz R, Scheuch H, Martin P. et al. c-Jun regulates eyelid closure and skin tumor development through EGFR signaling. Dev Cell 2003; 4: 879-889
• 8 Lee RT, Asharani PV, Carney TJ. Basal keratinocytes contribute to all strata of the adult zebrafish epidermis. PLoS One 2014; 9: e84858
• 9 Tawfik HA, Dutton JJ. Embryologic and Fetal Development of the Human Orbit. Ophthalmic Plast Reconstr Surg 2018; 34: 405-421
• 10 OʼRahilly R, Muller F. The development of the neural crest in the human. J Anat 2007; 211: 335-351
• 11 Byun TH, Kim JT, Park HW. et al. Timetable for upper eyelid development in staged human embryos and fetuses. Anat Rec (Hoboken) 2011; 294: 789-796
• 12 Barishak YR. Embryology of the eye and its adnexae. Dev Ophthalmol 1992; 24: 1-142
• 13 Koch KR, Ortmann M, Heindl LM. Conjunctival Mucoepidermoid Carcinoma. Ophthalmology 2016; 123: 616
• 14 Andersen H, Ehlers N, Matthiessen ME. et al. Histochemistry and development of the human eyelids. II. A cytochemical and electron microscopical study. Acta Ophthalmol (Copenh) 1967; 45: 288-293
• 15 Pearson AA. The development of the eyelids. Part I. External features. J Anat 1980; 130: 33-42
• 16 Sevel D. A reappraisal of the development of the eyelids. Eye (Lond) 1988; 2 (Pt 2): 123-129
• 17 Lyons CJ, Rosser PM, Welham RA. The management of punctal agenesis. Ophthalmology 1993; 100: 1851-1855
• 18 Ali MJ, Kakizaki H. Embryology of the lacrimal drainage system. In: Ali MJ. ed. Principles and practice of lacrimal surgery. Singapore: Springer; 2018: 9-18
• 19 Rodini E, Freitas J, Richieri-Costa A. Rapp-Hodgkin syndrome: report of a Brazilian family. Am J Med Genet 1990; 36: 463-466
• 20 Vila-Coro AA, Arnoult JB, Robinson LK. et al. Lacrimal anomalies in Brachmann-de Langeʼs syndrome. Am J Ophthalmol 1988; 106: 235-237
• 21 Vila-Coro AA, Mazow ML, Drtil SH. et al. Lacrimal anomalies in Robinowʼs syndrome. Arch Ophthalmol 1988; 106: 454
• 22 Gupta S, Ali MJ, Naik MN. Lacrimal drainage anomalies in congenital rubella syndrome. Clin Ophthalmol 2017; 11: 1975-1977
• 23 Pei YF, Rhodin JA. The prenatal development of the mouse eye. Anat Rec 1970; 168: 105-125
• 24 Tao H, Shimizu M, Kusumoto R. et al. A dual role of FGF10 in proliferation and coordinated migration of epithelial leading edge cells during mouse eyelid development. Development 2005; 132: 3217-3230
• 25 Harris MJ, Juriloff DM. Eyelid development and fusion induced by cortisone treatment in mutant, lidgap-Miller, foetal mice. A scanning electron microscope study. J Embryol Exp Morphol 1986; 91: 1-18
• 26 Knop N, Knop E. [Meibomian glands. Part I: anatomy, embryology and histology of the Meibomian glands]. Ophthalmologe 2009; 106: 872-883
• 27 Sevel D. The origins and insertions of the extraocular muscles: development, histologic features, and clinical significance. Trans Am Ophthalmol Soc 1986; 84: 488-526
• 28 von Goscinski C, Koch KR, Cursiefen C. et al. [Tumors of the lacrimal drainage system]. HNO 2016; 64: 386-393
• 29 Jin C, Yin F, Lin M. et al. GPR48 regulates epithelial cell proliferation and migration by activating EGFR during eyelid development. Invest Ophthalmol Vis Sci 2008; 49: 4245-4253
• 30 Martin P, Parkhurst SM. Parallels between tissue repair and embryo morphogenesis. Development 2004; 131: 3021-3034
• 31 Zhang H, Hara M, Seki K. et al. Eyelid fusion and epithelial differentiation at the ocular surface during mouse embryonic development. Jpn J Ophthalmol 2005; 49: 195-204
• 32 Ohuchi H. Wakayama Symposium: Epithelial-mesenchymal interactions in eyelid development. Ocul Surf 2012; 10: 212-216
• 33 Pearson AA. The development of the eyelids. Part I. External features. J Anat 1980; 130: 33
• 34 Byun TH, Kim JT, Park HW. et al. Timetable for upper eyelid development in staged human embryos and fetuses. Anat Rec (Hoboken) 2011; 294: 789-796
• 35 Meng Q, Mongan M, Carreira V. et al. Eyelid closure in embryogenesis is required for ocular adnexa development. Invest Ophthalmol Vis Sci 2014; 55: 7652-7661
• 36 Kudryavtseva EI, Sugihara TM, Wang N. et al. Identification and characterization of Grainyhead-like epithelial transactivator (GET-1), a novel mammalian Grainyhead-like factor. Dev Dyn 2003; 226: 604-617
• 37 Ting SB, Caddy J, Hislop N. et al. A homolog of Drosophila grainy head is essential for epidermal integrity in mice. Science 2005; 308: 411-413
• 38 Ting SB, Wilanowski T, Cerruti L. et al. The identification and characterization of human Sister-of-Mammalian Grainyhead (SOM) expands the grainyhead-like family of developmental transcription factors. Biochem J 2003; 370: 953-962
• 39 Yu Z, Lin KK, Bhandari A. et al. The Grainyhead-like epithelial transactivator Get-1/Grhl3 regulates epidermal terminal differentiation and interacts functionally with LMO4. Dev Biol 2006; 299: 122-136
• 40 Yu Z, Bhandari A, Mannik J. et al. Grainyhead-like factor Get1/Grhl3 regulates formation of the epidermal leading edge during eyelid closure. Dev Biol 2008; 319: 56-67
• 41 Wankell M, Munz B, Hubner G. et al. Impaired wound healing in transgenic mice overexpressing the activin antagonist follistatin in the epidermis. EMBO J 2001; 20: 5361-5372
• 42 Hsu SY, Kudo M, Chen T. et al. The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7. Mol Endocrinol 2000; 14: 1257-1271
• 43 Alazami AM, Shaheen R, Alzahrani F. et al. FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome. Am J Hum Genet 2009; 85: 414-418
• 44 Whitnall SE. A Ligament acting as a Check to the Action of the Levator Palpebrae Superioris Muscle. J Anat Physiol 1911; 45: 131-139
• 45 Findlater GS, McDougall RD, Kaufman MH. Eyelid development, fusion and subsequent reopening in the mouse. J Anat 1993; 183 (Pt 1): 121-129
• 46 Kapalanga J, Blecher SR. Histological studies on eyelid opening in normal male mice and hemizygotes for the mutant gene Tabby (Ta) with and without epidermal growth factor treatment. Exp Eye Res 1991; 52: 155-166
• 47 Mohamed YH, Gong H, Amemiya T. Role of apoptosis in eyelid development. Exp Eye Res 2003; 76: 115-123
• 48 Birnholz JC. Ultrasonic fetal ophthalmology. Early Hum Dev 1985; 12: 199-209
• 49 Petrikovsky BM, Kaplan G, Holsten N. Eyelid movements in normal human fetuses. J Clin Ultrasound 2003; 31: 299-301