April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
Constitutive Activation of Notch Pathway Disrupts Eyelid Morphogenesis During and Following Mouse Development
Author Affiliations & Notes
  • C.-Y. Liu
    Ophthalmology, Univ of Cincinnati, Cincinnati, Ohio
  • Y. Zhang
    Ophthalmology, Univ of Cincinnati, Cincinnati, Ohio
  • W. W. Y. Kao
    Ophthalmology, Univ of Cincinnati, Cincinnati, Ohio
  • Footnotes
    Commercial Relationships  C.-Y. Liu, None; Y. Zhang, None; W.W.Y. Kao, None.
  • Footnotes
    Support  NIH grants EY12486 and EY13755; Research to Prevent Blindness; Ohio Lions Foundation for Eye Research
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 3491. doi:
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    • Get Citation

      C.-Y. Liu, Y. Zhang, W. W. Y. Kao; Constitutive Activation of Notch Pathway Disrupts Eyelid Morphogenesis During and Following Mouse Development. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3491.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : In mammals, eyelids are of paramount importance for the formation of functional visual system, yet the cellular and molecular mechanisms underlying normal eyelid morphogenesis and homeostasis during and following development remain largely unknown. Notch signaling pathway plays a pivotal role in a wide variety of tissues morphogenesis and tumorigenesis. In the present study, we studied the effects of excessive Notch1 signaling activation in periocular mesenchymal cells of the cranial neural crest origin, which contribute to the formation of various ocular tissues, i.e., stromas of the eyelid, cornea, sclera, ciliary body and iris.

Methods: : Notch 1 intracellular domain (N1CD) was conditionally over-expressed in periocular mesenchymal cells of Kera-rtTA/tetO-Cre/RosaN1CD (KR/TC/RosaN1CD) triple transgenic mice treated with doxycycline (Dox) at different developmental stages, e.g., E14.5 (embryonic day 14.5) and post-natal day 2 (P2). The phenotypes of neonates were examined by histology and immunohistochemistry.

Results: : These triple KR/TC/RosaN1CD mice exhibited variegation of eyelid anomalies depending on the age of initial Dox induction. When Dox was administered to embryonic at E14.5, eyelid open at birth (EOB) phenotype was observed and animals suffered secondary exposure keratitis due to the malformation of tarsus and Meibomian glands. Interestingly, if Dox induction commenced at P2 at a time when eyelid closure had happened, the eyelid opening was much delayed and never reached full opening in these mice in comparison with the wild-type littermates. This phenotype resembles human congenital ptosis. Immunohistochemical analyses revealed that both Jagged and Notch1 were detected on the cytoplasmic membrane of the periocular mesenchymal cells of wild type mice, in contrast, Notch1 immunoreactivity was found mainly in the nuclei of these cells in the mutant mice. It is noteworthy that muscle differentiation marker genes, myoD, myogenein, and alpha-smooth actin expression were down-regulated.

Conclusions: : The observation implicates that constitutive Notch signaling may have perturbed myogenic differentiation of the periocular mesenchymal cells of neural crest origin, leading to the interruption of fetal eyelid closure during embryonic development and its postnatal re-opening. Thus, the KR/TC/RosaN1CD triple transgenic mouse may be a novel model for examining the pathogenesis of EOB and congenital ptosis.

Keywords: eyelid • signal transduction • development 
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